Enzymology of mitochondrial DNA repair

CHAPTER EIGHT

Enzymology of mitochondrial DNA repair Rebeca R. Alencar, Caio M.P.F. Batalha, Thiago S. Freire, Nadja C. de Souza-Pinto* Departamento de Bioquı´mica, Instituto de Quı´mica, Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil *Corresponding author: e-mail address: [email protected]

Contents 1. The mitochondrial genome 2. Enzymes of direct damage reversal 3. The base excision repair pathway 3.1 Step 1: Recognition and removal of damaged base 3.2 Step 2: End processing 3.3 Step 3: Gap filling/ligation 4. Types of damage processed by mtBER 5. The mismatch repair pathway 6. The nucleotide excision repair pathway 7. DNA double strand break repair 7.1 Nonhomologous end joining 7.2 Homologous recombination Acknowledgments References

258 259 261 263 265 266 267 269 271 273 273 275 277 277

Abstract The mitochondrial genome encodes proteins essential for the oxidative phosphorylation and, consequently, for proper mitochondrial function. Its localization and, possibly, structural organization contribute to higher DNA damage accumulation, when compared to the nuclear genome. In addition, the mitochondrial genome mutates at rates several times higher than the nuclear, although the causal relationship between these events are not clearly established. Maintaining mitochondrial DNA stability is critical for cellular function and organismal fitness, and several pathways contribute to that, including damage tolerance and bypass, degradation of damaged genomes and DNA repair. Despite initial evidence suggesting that mitochondria lack DNA repair activities, most DNA repair pathways have been at least partially characterized in mitochondria from several model organisms, including humans. In this chapter, we review what is currently known about how the main DNA repair pathways operate in mitochondria and contribute to mitochondrial DNA stability, with focus on the enzymology of mitochondrial DNA repair.

The Enzymes, Volume 45 ISSN 1874-6047 https://doi.org/10.1016/bs.enz.2019.06.002

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2019 Elsevier Inc. All rights reserved.

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1. The mitochondrial genome The mitochondrial genome is a circular double-stranded DNA molecule, reminiscent of the genome of the α-protobacteria which originated mitochondria. In most species, the mitochondrial DNA (mtDNA) encodes only a few proteins, all components of the oxidative phosphorylation (OXPHOS) system, and the rRNAs and tRNAs required for intraorganellar protein synthesis. In mammals, the mtDNA encodes 13 polypeptides, subunits of OXPHOS Complexes I, III, IV and V [[1], revised by [2]]. MtDNA stability is essential for proper mitochondrial function. Over 150 inherited pathogenic mutations have been mapped in the human mtDNA, causing an array of clinically diverse syndromes. In addition, stochastic accumulation of somatic mutations, particularly in postmitotic tissues, has been proposed to play a role in aging, cancer and neurodegenerative diseases [3]. The mtDNA accumulates mutations faster than the nuclear DNA (nDNA). Although the ratio of mtDNA over nDNA mutations is highly variable among animal taxa, it is always higher in mtDNA [4]. It was initially proposed that high exposure to reactive oxygen species (ROS) and poor repair system would account for the elevated mutagenesis of the mtDNA; however, recent findings, including mutation signatures not compatible with oxidative stress-induced DNA damage and the characterization of robust DNA repair systems, as discussed here, suggested that the reasons for this elevated mutagenesis are not as straightforward as previously thought, and that replication errors may contribute significantly to mtDNA mutation accumulation [5]. Nonetheless, the role of damage accumulation and/or faulty DNA repair in mtDNA instability has been demonstrated and is thought to be physiologically relevant in the context of human diseases [6]. The mtDNA is localized in the mitochondrial matrix, in a nucleoproteic complex known as the mitochondrial nucleoid, which is physically associated with the inner side of the inner mitochondrial membrane, and although the exact contact sites are still unknown, the inner membrane protein Mic60/Mitofilin is required for proper nucleoid organization in mammalian mitochondria [7]. In the nucleoid, the mtDNA is highly packed and covered with the mitochondrial transcription factor A (TFAM), which binds cooperatively to mtDNA, in a sequence unspecific manner, resulting in highly compacted DNA molecule [8,9].

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The nucleoid structure, with the mtDNA “buried” in the protein complex, has been proposed to protect it from DNA damage as it would limit access to damaging agents. In fact, overexpression of TFAM decreased mtDNA damage and prevented cellular dysfunction in a diabetic neuropathy animal model [10] and in a cellular model of MPTP neurotoxicity [11], reinforcing the idea that this structure protects the mtDNA. On the other hand, in vitro TFAM binding to DNA hampers access to DNA repair enzymes [12] and mitochondrial base excision repair activities are physically associated with the nucleoid [13], suggesting that nucleoid remodeling is required for proper mtDNA repair. Several proteins have been associated with nucleoid remodeling in the context of mtDNA transcription and replication, but little is still known in the context of DNA repair. Next, we summarize the current knowledge about DNA repair pathways in mitochondria, mostly in mammalian systems, but also in different model organisms, when available. Because the focus of this review is on mitochondrial DNA repair, mechanistic detail on nuclear pathways are presented only when needed to contextualize what is known in mitochondria.

2. Enzymes of direct damage reversal The simplest way to repair DNA damage is by direct damage reversal, in which a single enzyme restores the damaged base without excision of the base or the phosphodiester backbone. Damage reversal enzymes are found in all domains of life, including in some viruses. Direct damage reversal has been demonstrated for UV-induced photolesions, cyclobutane pyrimidine dimers and 6,4-photoproducts, through photolyases, and alkylation damage (mostly methylations) through the activities of alkyltransferases for O-alkylated DNA bases and the AlkB family of dioxygenases for N-alkylated bases (mechanistic details can be found in Ref. [14]). Photolyases reverse pyrimidine dimers through a FADH-dependent cleavage of the covalent bond in a light dependent mechanism. Photolyases are damage specific, with CPD-photolyases cleaving only cyclobutane pyrimidine dimers and 6,4-PP photolyases only the pyrimidine-pyrimidone product. Photolyases are found in most taxa, with the notable exception of placental mammals. Nonetheless, mitochondrial localization of photolyases has been described only in plants, where a mitochondrial CPD-photolyase has been identified in rice [15], and a Arabidopsis thaliana 6,4-PP-photolyase was recently found to localize to mitochondria and chloroplasts [16].

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However, it should be noted that of two mouse photolyase-like genes cloned, mCRY1 (mPHLL1) and mCRY2 (mPHLL2), mCRY1 is localized in mitochondria [17]. CRY1 has been identified as a component of the mammalian circadian clock, but a specific role in repair of photolesions has not been demonstrated. The AlkB family of dioxygenases remove alkyl adducts from bases by a Fe- and α-ketoglutarate dependent oxidative dealkylation. These enzymes are ubiquitous and conserved from bacteria to mammals, acting in both DNA and RNA repair with a wide range of methylated purines as substrate (for mechanistic details, see Ref. [18]). Nine mammalian homologues of the prototypical E. coli AlkB have been identified, although not all have been shown to have DNA repair activity. Of these, ALKB1 (hABH1) has been localized to mitochondria in human cells. In vitro assays with recombinant ALKB1 showed a demethylase activity on 3-methylcytosine in both single-stranded DNA and RNA, implicating the protein in DNA repair of alkylation damage but possibly also in regulating levels of 3-MeC in tRNAs an rRNAs [19]. No other AlkB homologue has been conclusively localized to mitochondria, even though alkbh7
/
mice missing the ALKBH7 protein accumulate more mtDNA damage than their wildtype counterparts, suggesting that ALKBH7 could also be directly involved in mtDNA repair [20]. Among the variety of lesions generated by alkylating agents, O6methylguanine is a highly mutagenic modification, which seems to be repaired almost exclusively by direct damage reversal catalyzed by O6methylguanine methyl transferase (MGMT). MGMT is a suicide enzyme that accepts the methyl-group in a catalytic cysteine residue, restoring the guanine base [21]. MGMT is frequently found mutated in tumors but also associated with chemotherapy resistance in glioblastomas [22]. Bona fide mitochondrial localization of MGMT has not been demonstrated yet, although alkylation damage is repaired from human and mouse mtDNA, likely by the alkyladenine DNA glycosylase (AAG) through the base excision repair (BER) pathway, as discussed ahead. However, therapeutic strategies targeting MGMT to mitochondria by fusing a mitochondrial targeting sequence have shown that mitochondrial localization of MGMT protects human cells from alkylation damage [23,24], underscoring the role of alkylation damage to mtDNA in cytotoxicity of alkylating agents, a clinically relevant class of chemotherapeutic agents. In addition to damage reversal, lesion bypass is a “damage tolerance” mechanism which allows replication and transcription to proceed past

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the damage site. The replicative mitochondrial DNA polymerase, pol γ, can bypass several types of damage including 7,8-dihydro-8-oxo-20 deoxyguanosine (8-OHdG), benzopyrene adducts, UV-induced pyrimidine dimers and acrolein adducts, although in an error-prone fashion [25]. Nonetheless, oxidized lesions stall the mitochondrial replisome in vitro [26], even in presence of PrimPol, a proposed mitochondrial translesion synthesis DNA polymerase, which will be further discussed in chapter “Mechanism of DNA primer synthesis by human PrimPol” by Blanco et al. in this volume. Plant organellar polymerases also display lesion bypass activity across an apurinic/apyrimidinic site (AP site) [27]. Lesion bypass by the mitochondrial RNA polymerase during RNA synthesis has been poorly studied, but one report showed that purified mtRNAP bypasses the oxidized bases 8-OHdG and thymine glycols, but not UV-induced photolesions and AP sites [28].

3. The base excision repair pathway The BER pathway has evolved to remove small chemical and structural modifications that do not cause significant distortion in the double helix but that, if unrepaired, might lead to cytotoxicity or mutagenesis. The types of DNA modifications processed by the BER pathway are discussed in more detail ahead. BER is present both in the nucleus and in the mitochondria, where it is the predominant DNA repair pathway, as well as the most studied. It functions very similarly in both compartments, with just a few differences. In the nucleus, it is mainly active during the G1 phase of the cell cycle [29]. It was the first DNA repair pathway discovered in mitochondria [30], and, in this compartment, it has a very important role in repairing damage caused by ROS, a crucial task, given that mitochondria are the main ROS generators in the cell. This pathway has a very minimalistic and intuitive setup and is evolutionarily conserved from bacteria to humans [31,32]. Even though all DNA repair pathways are important for the adequate functioning of cells, BER seems to be crucial, because, with the exception of the DNA glycosylases that have overlapping substrate specificity, deletion of the genes coding for any of the other BER core components results in embryonic lethality in mice [33–37]. While most mtBER enzymatic components have been relatively well characterized, the mechanisms involved in their regulation are not completely elucidated, with little known so far of how

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posttranslational modifications and protein-protein interactions regulate activity and BER subpathway choices. For instance, the observation that p53 can modulate mtBER activity [38] suggests that proteins involved in DNA damage response in the nucleus might have analogous roles in mitochondria. Mechanistically, the BER pathway can be roughly divided in three stages: (i) recognition and removal of damaged base, (ii) end processing, and (iii) gap filling/ligation. Before going into details of the mechanistic aspects of each enzymatic reaction in the pathway, it is useful to present an overall schematic of how the pathway works, so the reader will be able to understand each enzymatic reaction in the more general context of what the pathway is supposed to do. BER begins with the detection of the modified base by one of the several DNA glycosylase enzymes. The modified base is released by the hydrolytic cleavage of the N-glycosyl bond, leaving an AP-site. This AP-site is then cleaved by an endonuclease or an AP-lyase activity, forming a single-strand break. Depending on the nature of the 30 and 50 ends, at this point BER can proceed through one of two subpathways. If the AP-site cleavage resulted in a 30 -OH and 50 -deoxyribose-phosphate (50 -dRP), a DNA polymerase fills in the gap and processes the 50 -dRP, in what is known as short-patch BER (SP-BER). If the cleavage resulted in a modified 50 end, more nucleotides (up to 8–10) are incorporated, displacing the opposite strand, in what is known as long-patch BER (LP-BER). This displaced strand is then cleaved at the junction by a structure-specific endonuclease. Both subpathways end with a DNA ligase connecting the two strand ends. As it can be appreciated, the BER pathway is mechanistically simple, consisting of only five sequential reactions. In fact, this pathway can be reconstituted in vitro with only four enzymes [39], as some DNA glycosylases have, in addition to their glycosylase activity, an associated AP-lyase activity that allows them to cut the AP-site, thus eliminating the need for another endonuclease in the second step of the pathway. This class of glycosylases, which have both glycosylase and AP-lyase activity, is called bifunctional glycosylases, as opposed to monofunctional glycosylases, which only have glycosylase activity, and, therefore, require an endonuclease for the pathway to proceed. Both nuclear and mitochondrial BER follow the same logic, differing only in some details. A more detailed description of each step of the BER pathway is given bellow, highlighting the enzymes involved in mitochondrial BER.

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3.1 Step 1: Recognition and removal of damaged base As with any DNA repair pathway, BER begins with the detection of the DNA modification. This step is accomplished by a family of enzymes called DNA glycosylases [40]. There are 11 known DNA glycosylases in humans, each responsible for the recognition and removal of subset of DNA modification, although with some overlap in the substrates they can recognize. Such redundancy might explain why they are the only components of the pathway that when deleted do not cause embryonic lethality in mice. All DNA glycosylases previously localized in the nucleus, with the exception of SMUG1, TDG, MBD4 and NEIL3, have also been identified in mitochondria [41] (Table 1). In several cases, the mitochondrial isoforms of the different DNA glycosylases are distinct from their nuclear counterparts. The human UNG gene encodes two major isoforms of the uracil DNA glycosylase (UDG), UNG1 (mitochondrial) and UNG2 (nuclear) [42], generated by alternative splicing and transcription from different positions in the UNG gene [43]. For the human oxoguanine DNA glycosylase (OGG1) gene, seven alternatively spliced mRNAs were identified, with two major polypeptides being detected: OGG1α (nuclear and mitochondrial) and OGG1β (mitochondrial) [44,45]. The mouse OGG1, on the other hand, has only one isoform identified. The MutY homologue DNA glycosylase (MUTYH) has 10 isoforms, generated by alternative splicing of its three main transcripts: α, β and γ. It is believed that the mitochondrial isoform originates from the α1 transcript, and the nuclear isoforms from the β1, β3 or γ2 transcripts. In the case of methyl(alkyl)purine DNA glycosylase (MPG or AAG), three transcriptional isoforms have been detected, A, B and C, of which at least A and B have a putative mitochondrial tagging sequence and have been localized to mitochondria [46]. As for the endonuclease III-like (NTH1), endonuclease VIII-like glycosylases 1 (NEIL1) and 2 (NEIL2), their mitochondrial localization and activity have been demonstrated in mitochondrial extracts [45,47,48]. However, their mitochondrial isoforms have not been properly characterized. DNA glycosylases use a flipping-out mechanism to detect and remove the altered base that relies on the stability of the unmodified base-pairings that will not flip-out of the double-strand. With a modified base, however, the pairing is not optimal, and the enzyme manages to flip the base, which is then positioned in the catalytic site of the DNA glycosylase [49]. If the modification in the base makes contact with specific residues in the catalytic site, then the N-β-glycosydic bond between the base and the sugar moiety is cleaved due to a nucleophilic attack on the 10 -carbon of the sugar

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moiety [49], resulting in the abasic site. In monofunctional glycosylases, this catalysis is accomplished by a water molecule activated by an aspartate residue. In bifunctional glycosylases, the aspartate residue activates a lysine, forming an intermediate Schiff base [50]. The Schiff base is then resolved either by β-elimination (e.g., NTHL1) or β/δ-elimination (e.g., NEIL1) [51], leaving strand ends that will require some processing before proceeding with the subsequent BER steps. Monofunctional glycosylases are displaced from the abasic site by AP endonuclease 1 (APE1), which hydrolyzes the AP site, generating a single-strand break with a 30 -OH terminal on one end, and a 50 -dRP terminal on the other end. Table 1 summarizes the localization and mechanistic details for all human DNA glycosylases known to date.

Table 1 End processing characteristics of DNA glycosylases. DNA Mitochondrial AP-lyase glycosylase localization Type activity

SMUG1 TDG





M M





30 End

50 End

30 Processing 50 Processing

30 OH

50 dRP

0

3 OH 0




Polβ

0




Polβ

0

5 dRP

MBD4 (MED1)




M




3 OH

5 dRP




Polβ

UNG (UDG)

+

M




30 OH

50 dRP




Polβ or Poly

MPG (AAG)

+

M




30 OH

50 dRP




Polβ or Poly

MUTYH (MYH)

+

M




30 OH

50 dRP




Polβ or Poly

OGG1

+

M/B β-lyase

30 -UHA 50 -PO4
APE1 0

0

-PO4






NTHL1 (NTH1)

+

B

β-lyase

NEIL1

+

B

β/δ-lyase 30 -PO4
50 -PO4
PNKP or APE1




NEIL2

+

B

β/δ-lyase 30 -PO4
50 -PO4
PNKP or APE1




NEIL3




M/B β/δ-lyase 30 -PO4
50 -PO4
PNKP or APE1




3 -UHA 5

APE1

30 -UHA, 30 unsaturated hydroxyaldehyde (30 -phospho-α, β-unsaturated aldehyde); B, bifunctional; M, monofunctional; M/B, can act either as monofunctional or bifunctional—following columns provide “ends” and “processing” of bifunctional activity.

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3.2 Step 2: End processing Depending on the DNA glycosylase employed, different types of 30 and 50 ends can be created, which require processing to generate the 30 -OH and 50 phosphate termini to allow for polymerization and ligation. Therefore, the “end processing” stage has the task of “cleaning” possibly blocking ends, so that the next enzymatic reactions can be carried out. If the glycosylase is monofunctional, APE1 is responsible for the endonuclease activity, both in the nucleus and mitochondria [52], and leaves a 30 OH terminus and a 50 -dRP terminus. In this case, no further processing of the 30 end is required. The 50 -dRP, on the other hand, is processed by the DNA polymerase, which, through its phosphodiesterase activity (dRPase) removes the 50 -dRP, generating 50 -phosphate. DNA polymerase β is the prototypical BER polymerase and carries out both polymerase and dRPlyase activities and is further discussed in chapter “DNA polymerase beta and other gap-filling enzymes in mammalian base excision repair” by Beard and Wilson in this volume. Pol γ also displays dRP-lyase activity and can support mtBER in vitro [53], although recently Pol β’s mitochondrial localization and role in mtBER has been demonstrated [54,55]. When the damage is removed by a bifunctional DNA glycosylase with β-lyase activity (OGG1 or NTHL1), the enzyme generates, through β-elimination, a 30 -end with an unsaturated hydroxyaldehyde (30 -phospho-α, β-unsaturated aldehyde), and a 50 -phosphate [51]. The processing of the 30 end is accomplished by the phosphodiesterase activity of APE1, restoring a 30 -OH. Bifunctional glycosylases with β/δ-lyase activity (NEIL1, NEIL2, NEIL3) will generate a 30 -phosphate and a 50 -phosphate, by cleaving the AP site on both sides and releasing an unsaturated deoxyribose as trans-4hydroxy-2,4-pentadienal [51]. The 30 -phosphate can then be removed by the polynucleotide kinase/phosphatase (PNPK), that has both a 50 -kinase and a 30 -phosphatase activity. APE1 can also remove the 30 -phosphate, although the 30 -phosphatase activity is not strong [56,57]. PNPK has been localized to mitochondria in human cells, physically associated with NEIL2 and pol γ. Moreover, PNPK-depleted mitochondrial extracts showed decreased BER and single-strand break repair activities, implicating PNPK in mtDNA repair [48]. Interestingly, OGG1 can act both as monofunctional or as bifunctional glycosylases, as APE1 displaces OGG1 from the abasic site intermediate [58]. Two highly specialized end-processing enzymes, aprataxin (APTX) and tyrosyl-DNA phsosphodiesterase 1 (TDP1), have also been involved in maintaining mtDNA stability, most prominently in the repair of

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single-strand breaks. APTX, which removes blocking 50 adenylated-deoxyribose phosphate (50 -AMP-dRP) lesions that arise from aborted ligation reactions, has been localized to mitochondria in human cells, and APTX depletion results in mitochondrial bioenergetic dysfunction and decreased mtDNA copy number [59]. Cells deficient in APTX show impaired mitochondrial function and morphology, and lower expression of the mitochondrial fusion protein OPA1, underlying APTX’s role in mtDNA stability [60]. Nonetheless, pol β lyase activity was able to remove the 50 -AMP-dRP group in mitochondrial extracts from APTX
/
cells [61], suggesting that complementing pathways act to protect mtDNA from these blocking lesions. TDP1 hydrolyzes the phosphodiester bond between a tyrosyl moiety and a DNA 30 -end [62] and has been implicated in the repair of stalled Top1DNA covalent complexes, although the recombinant human protein has been shown to process a variety of 30 -end substrates [63]. A fraction of TDP1 was localized in mitochondria in human cells, and mtDNA from TDP1
/
cells accumulated more damage after H2O2 treatment compared to TDP1+/+ cells, suggesting a direct role in mtBER of oxidative damage [64]. Moreover, H2O2 and rotenone treatment induced translocation of TDP1 to mitochondria in yeast and mammalian cells, supporting its role in mtDNA repair [65].

3.3 Step 3: Gap filling/ligation After proper end processing, repair can be completed by nucleotide incorporation and ligation. In mammalian mitochondria, both the replicative mitochondrial polymerase, pol γ [53], and pol β [54,55] support BER nucleotide incorporation; however, the relative contribution of each polymerase for mtBER or mechanisms determining polymerase choice are not yet clear. At this point, BER can proceed, both in mitochondria and nucleus [66–69], through either SP-BER or LP-BER; although how subpathway choice is determined is not fully understood and is currently under intense investigation. Nonetheless, it should be noted that some modified ends, such as the 2-deoxyribonolactone-trapped pol γ, can be repaired only by LP-BER [67]. In the nucleus, SP-BER is the most prevalent choice in general, while LP-BER seems to be preferred during postreplicative repair [70,71], but no information is available on the relative contribution of SP- and LP-BER in mitochondria. In SP-BER, a single nucleotide is incorporated and the nick sealed by DNA ligase III (LIG3). In the nucleus, LIG3 exists always in complex with the X-ray Chinese hamster complementation group 1 (XRCC1) factor;

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however, no XRCC1 was detected in mitochondria and mitochondrial LIG3 activity was found to be independent of XRCC1 [72]. LIG3 is likely the only DNA ligase in mammalian mitochondria and, in fact, the embryonic lethality of LIG3 knockout mice was linked to its role in mtDNA maintenance rather than its role in nDNA repair [73,74]. In LP-BER, a short patch of 2–10 (nucleus) or 6–9 (mitochondria) nucleotides is incorporated [69]. This results in the displacement of the noncoding DNA strand ahead of the synthesis, creating a flap-like 3-strand structure, which is processed by the structure-specific endonucleases flap endonuclease 1 (FEN1) [67,75] aided by the DNA replication ATPdependent helicase/nuclease 2 (DNA2) [76,77], regenerating a ligatable 50 -phosphate end. Alternatively, EXOG (exo/endonuclease G) can also accomplish this step [78]. Fig. 1 illustrates the current model of BER pathway, indicating the main components implicated in nuclear and mitochondrial BER.

4. Types of damage processed by mtBER In general, BER repairs three main classes of base damage, deaminations, oxidations and alkylations, and single-strand breaks, through the single-strand break repair pathway (SSBR), which shares most enzymatic and mechanistic components with BER. The three glycosylases not detected in mitochondria (SMUG1, TDG and MBD4) are all involved in processing deamination products, leaving UDG as the sole representative of this class in the organelle. Thus far, AAG is the only DNA glycosylase identified in mitochondria which removes alkylated bases. All other mitochondrial DNA glycosylases process oxidized bases, which are the most prevalent type of base modification in mtDNA, given that mitochondria are the main cellular source of ROS (reviewed in Ref. [79]), and that it is closely located to the electron transport chain, where ROS are generated. A comprehensive review on the formation of oxidative DNA damage in the mtDNA can be found in Ref. [41]. Deamination refers to the spontaneous hydrolytic deamination of cytosine, turning it into deoxy-uracil, a noncanonical base in DNA. Because uracil pairs with adenine, if this U:G mismatch is not repaired before DNA replication, a C:G to T:A transition will occur. Additionally, dUTP might be erroneously incorporated instead of dTTP during replication, leading to U:A mismatches, that, although not necessarily mutagenic, can cause transcription factors to not recognize their binding sites.

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Fig. 1 Schematic representation of the Base Excision Repair (BER) pathway. The figure highlights the coordinated steps and catalytic components identified in SP- and LP-BER in nuclear (black) and mitochondrial (blue) DNA. The initial base damage is highlighted in red.

Alkylation can be caused by both exogenous and endogenous agents [80,81]. Exogenous factors include environmental toxins and chemotherapeutic agents, and endogenous ones include S-adenosylmethionine, which can methylate DNA nonenzymatically, and is present at a relatively high concentration inside mitochondria, with the organelles containing collectively approximately 30% of the cellular S-adenosylmethionine [82].

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Table 2 Types of lesions processed by mtDNA glycosylases. Type of DNA damage glycosylase Enzymatic substrates

Deamination UNG (UDG) U, 5-FU in ss and dsDNA Alkylation

MPG (AAG) 3-meA, 7-meG, 3-meG, Hx, εA in ss and dsDNA

Oxidation

MUTYH

A opposite 8-oxoG, C or G; 2-hA opposite G in dsDNA

OGG1

8-oxoG opposite to C, FaPyG opposite C in dsDNA

NTHL1

Tg, FaPyG, 5-hC, 5-hU in dsDNA

NEIL1

Tg, FapyG, FapyA, 8-oxoG, 5-hU, 5-hC in ss and dsDNA

NEIL2

Similar to NEIL1 and NTHL1

5-FU, 5-fluorouracil; 8-oxoG, 8-oxo-7,8-dihydroguanine; εA, ethenoadenine; A, adenine; C, cytosine; dsDNA, double-stranded DNA; FaPy, 2,6-diamino-4-hydroxy-5-N-methylformamidopyrimidine; G, guanine; h, hydroxyl; Hx, hypoxanthine; me, methyl; Tg, thymine glycol; ssDNA, single-stranded DNA; U, uracil.

Table 2 lists the base lesions known to be repaired by each mitochondrial DNA glycosylase. A more detailed review on the subject can be found in Ref. [83].

5. The mismatch repair pathway The mismatch repair (MMR) pathway repairs noncanonical base paring and insertion–deletion loops (IDLs). The nuclear MMR pathway is usually associated with the replication machinery and has been well characterized [84]. On the other hand, not much is still known about mitochondrial MMR, particularly regarding the biochemistry of mitochondrial MMR (mtMMR). Nonetheless, mitochondrial DNA microsatellite instability, a hallmark of MMR defects, is found in several tumors [85], but rarely associated with mutations in MMR genes, suggesting that the mtMMR machinery might be distinct from that of nuclear MMR [86]. The first evidence that mitochondria contain mismatch repair activities was obtained in yeast, with the cloning and characterization of a MutS

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homologue, ScMSH1, which localized to mitochondria [87]. Msh1 deficient yeast strains showed increased mtDNA mutations and large-scale rearrangements [88,89], and strong instability in poly-GT tracts [90], implicating MSH1 in mtDNA stability. Purified yeast MSH1 hydrolyzes ATP and binds to DNA substrates containing mismatches and unpaired nucleotides, with a substrate specificity similar to that of bacterial MutS [91]. In addition to its role in mtMMR, ScMSH1 has been directly implicated in repair of oxidative damage in the mtDNA [89,92] through a role in base excision repair [93], and in large-scale recombination of the mtDNA [94]. MutS homologues have also been found in the coral Sarcophyton glaucum plants [95], in Arabidopsis thaliana [96] and Toxoplasma gondii [97]. AtMSH1 has been implicated in mtDNA copy number maintenance [96] and recombination [98]. Unlike MutS and mammalian homologues, AtMSH1 has a C-terminal homing endonuclease domain, required for its function [99]. More recently, it has been shown that AtMSH1 localizes to both mitochondria and plastids and influences plastid DNA stability [100]. A DNA binding activity of AtMSH1 has been also recently demonstrated [101]. A moss MSH1 also localizes to mitochondria and shows genetic interaction with the recombination factors RecA and RecG to maintain mtDNA stability [102]. MutS and most of its eukaryotic homologues are arranged in five structural domains, of which domains I and IV interact with DNA and domain V harbors the ATPase activity and the dimerization interface [103]. The Toxoplasma MSH1 (TgMSH1) contains only domains I and V, and shares AtMSH1 C-terminal endonuclease domain. Interestingly, TgMSH1 disruption leads to a multidrug-resistance phenotype [97], and accumulation of single nucleotide variations in mitochondrial DNA and lower mtDNA content [104]. Mitochondrial extracts from rat liver [105,106] or human cell lines [107] support mismatch correction in in vitro assays. In the mammalian nucleus, MMR is initiated by damage recognition by the MutSα (MSH2-MSH6) or MutSβ (MSH2-MSH6) heterodimers [108]. However, mitochondrial localization of MSH2 has not been clearly demonstrated in mammalian mitochondria. Although one study suggested that rat liver mitochondria may contain MSH2 [105], mitochondrial extracts from MSH2-deficient cells showed similar mismatch-binding activity [107], suggesting that mtMMR is independent of MSH2. Recently, a synthetic lethality interaction between polγ and MLH1, a component of the MutLα complex which stabilizes the MutSα-DNA

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complex, was observed in human cells, which was rescued by overexpression of mitochondrial but not nuclear OGG1, suggesting a role for MLH1 in mtDNA maintenance [109]. In addition, MLH1 overexpression decreased accumulation of D-loop sequence variants in retinal endothelial cells from a diabetic rat model [110]. However, mitochondrial localization of the protein has not yet been demonstrated. We have identified the Y-box binding protein 1 (YB-1) as a putative mismatch binding factor in human mitochondrial extracts [107]. Soluble proteins from YB-1-depleted mitochondrial extracts bind less efficiently to mismatches and insertion-deletion loops and display lower mismatch correction activity in vitro, which is complemented by recombinant YB-1. This protein has been shown to have other functions in DNA repair, as it stimulates the BER proteins NEIL-2 [111] and APE1 [112], promotes lesion recognition by the XPC-HR23B complex in NER [113], and inhibits nuclear MMR activity by disrupting Mutsα-DNA interaction [114]. However, its role in mtMMR has not been further investigated and other factors involved have not yet been characterized biochemically.

6. The nucleotide excision repair pathway The first attempt to detect DNA repair in mitochondria analyzed removal of UV-induced damage, the prototypical Nucleotide Excision Repair (NER) substrate, from mtDNA and found that these lesions were not removed at significant rates in mammalian [115] or yeast cells [116], leading to the long-standing notion that mitochondria lacked DNA repair systems. In fact, to date no clear evidence of canonical NER in mitochondria has been published (for mechanistic details on nuclear NER, please see chapter “Damage removal and gap filling in nucleotide excision repair” by Kemp in this volume). But while some lesions typically removed by NER is the nucleus, like aflatoxin B1-adducts, remain in rat liver mtDNA for over 24 h [117], others like 4-Nitroquinoline 1-oxide-adducts and cisplatin interstrand crosslinks, disappear from mtDNA over time [118,119], possibly due to replication-associated dilution or mtDNA degradation (for more on this topic, see chapter “Mitochondrial DNA degradation: A quality control measure for mitochondrial genome maintenance and stress response” by Zhao in this volume). But despite the apparent lack of a complete NER pathway in mitochondria, NER factors have been localized to mitochondria in mammalian cells. The first evidence of a mitochondrial role for NER factors was the

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observation that 8-OHdG removal was impaired in cells deficient in the transcription-coupled NER protein CSB, that is mutated in Cockayne syndrome (CS) [120]. CSB and CSA, another transcription-coupled NER factor mutated in CS, localize to mitochondria in human cells, where they promote mtDNA repair through direct association with OGG1 [121] and by maintaining mtBER association with the inner mitochondrial membrane [122], which is relevant in the context of the localization of the mtDNA. Mitochondrial CSB has also been shown to promote mtDNA transcription elongation [123]. In addition to direct roles in mtDNA maintenance, CSB deficiency in human cells has been linked to impaired mitophagy [124] and altered redox balance [125,126]. Collectively, these observations suggest that mitochondrial dysfunction, due to increased mtDNA damage and redox imbalance, may contribute significantly to the pathophysiology of CS (for review, see Ref. [127]). More recently, the TFIIH component XPD has also been localized to human mitochondria [128]. XPD is actively recruited to mitochondria upon oxidative stress and XPD-deficient cells accumulate more mtDNA deletions after H2O2 treatment than XPD-proficient or complemented cells, thus implicating mitochondrial XPD in repair of oxidatively induced damage. Whether this is through a role of XPD in mtBER is still unknown, but it should be noted that among the cell lines deficient in the NER proteins XPA, XPB and XPD, XPD-deficient lymphoblastoid cells are the most sensitive to H2O2 induced genomic instability [129]. Aside from the core NER components (XP proteins and associated factors) many other proteins have been implicated in different roles in NER, including several helicases of the RecQ family [130]. The RecQ family of helicases is composed of nine members, five of which are found in humans, and at least three human premature aging syndromes are caused by mutations in RecQ helicases. RECQL4, mutated in the Rothmund-Thomson Syndrome, has also been detected in mitochondria. RECQ4L-deficient cells accumulated mtDNA damage [131], and ectopic expression of RECQL4 increased mtDNA copy number in HEK293 cells [132]. Interestingly, the RECQ4L-p53 physical interaction was shown to be important for p53 mitochondrial localization, even in absence of DNA damage [133]. In the nucleus, several reports have linked the tumor suppressor protein p53 to NER activity, as it was initially shown that p53 modulates NER activity through a physical interaction with several TFIIH components [134]. Although p53 translocates to mitochondria after several

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death-associated stresses, including DNA damage-inducing agents [135], in this organelle, however, p53 stimulates BER, through a functional interaction with pol γ [38,136,137]. Moreover, p53 mitochondrial translocation upon exercise decreases mtDNA mutational load in a pol γ-proof-reading deficient mouse model that accumulates high levels of mtDNA mutations [138], highlighting the p53-pol γ functional interaction in mtDNA repair. Lastly, it is notable that whereas many NER factors do not appear to have a role in mtDNA repair, mitochondrial dysfunction is observed in NERdeficient cells, and may contribute to the pathophysiology of DNA repair disorders. A comprehensive review on the subject can be found in Ref. [127].

7. DNA double strand break repair DNA double-strand breaks (DSBs) are considered among the most deleterious lesions to the cell. In eukaryotic cells, at least four mechanistically distinct pathways to repair DSBs (DSBR) have been characterized, nonhomologous DNA end joining (NHEJ), alternate end joining (a-EJ), homologous recombination (HR), and single-strand annealing (SSA). In normal cells, most DSBs generated in nuclear DNA are repaired by NHEJ or HR, depending largely on the phase of the cell cycle. NHEJ and its variations, a-EJ and SSA, are considered error-prone pathways, as the initial processing of the DSB results in sequence loss; HR, on the other hand, is a faithful pathway, relying on sister chromatid homology to repair DSBs (for review, see Ref. [139]). Due to the circular nature of the mtDNA molecule, DSBs result in linear fragments of DNA. These fragments have been shown to be degraded rapidly by the exonuclease activity of pol γ [140], and indeed, induced DSBs in mtDNA lead to an overall drastic decrease of mtDNA content in the mitochondria [141]. Moreover, DSBR generates mtDNA variability in Arabidopsis, and drives evolution of the mitochondrial genome [142].

7.1 Nonhomologous end joining In the nucleus, the first event in classical NEHJ (c-NHEJ) is end-binding by the Ku heterodimer, Ku70/Ku80, which is thought to protect the ends and keep them close for further ligation. This complex is integral to the c-NHEJ pathway, as it recognizes and binds to DSB ends, recruiting other repair proteins to the damage site [143]. In Saccharomyces cerevisiae, mutants with a

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Ku70/80 deletion have significantly higher rates of mtDNA deletions when compared to wild-type strains, indicating that these proteins may play a role in mtDNA integrity [144]. In mammalian cells, an alternate form of Ku80 lacking a C-terminal epitope is detected in mitochondria and displays DNA end-binding activity [145], suggesting that these proteins are involved in mtDNA dynamics, possibly binding and recognizing broken DNA ends. And although no mitochondrial localization of Ku70 has been reported, Ku70 has been found in the cytoplasm, where it binds to Bax and suppresses its mitochondrial translocation upon apoptotic signaling [146]. Notably, stability of each subunit depends on the other, and knockout of either or both cause a similar phenotype in mice [147], suggesting that both subunits would likely be required for mitochondrial NHEJ. After Ku binding to the ends, the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which together with Ku forms the full DNAdependent protein kinase (DNA-PK), Artemis, a nuclease whose activity is regulated by DNA-PKcs-mediated phosphorylation, and DNA ligase IV, are recruited to carry out the repair of the breaks [148,149]. There is currently no evidence suggesting that these enzymes are present in mammalian mitochondria. Furthermore, it has been demonstrated that mammalian mitochondrial extracts from various tissues do not possess the machinery to repair DSBs through classical NHEJ in vitro at the same concentrations at which whole cell extracts are able to do so proficiently [150]. Thus, at present, it not clear whether c-NHEJ operates in and is relevant for mtDNA maintenance. As opposed to NHEJ, the a-EJ pathway, also known as microhomologymediated end joining (MMEJ), utilizes microhomologous sequences (5–16 bp) to repair DSBs independent of c-NHEJ proteins such as Ku70/ 80 [151]. In MMEJ, poly-ADP-ribose polymerase (PARP1) acts as the DSB sensor, competing with Ku70/80 to occupy and repair DSBs through the two different pathways [152,153]. PARP1 has been shown to localize within the mitochondria, associating with mtDNA and participating in mitochondrial genome maintenance [154]. PARP1 is involved in DSB recognition and also in recruiting the MRN (Mre11-Rad50-Nbs1)-CtIP complex to the site of the DSB [155]. This complex introduces a nick near the DSB and anneals through the 30 -50 exonuclease activity of Mre11, an endresection priming step that exposes the microhomologous ends for annealing [151,155]. Mre11, which forms the core of the MRN complex, has been shown to be present in mammalian mitochondria, colocalizing with and binding to mtDNA [156]. Mre11p and Rad50p are both present in the

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Saccharomyces cerevisiae mitochondrial proteome, suggesting that these proteins function within the yeast mitochondria [157]. The FEN1 flap endonuclease, which localizes to mitochondria and is involved in mitochondrial LP-BER [67] is also implicated in MMEJ, possibly cleaving the 50 flap at DSBs [158]. The DNA ligase that performs the ligation step of MMEJ in the nucleus is DNA ligase III, which is also present in the mitochondria as the sole ligase in the organelle. The presence of these various MMEJ enzymes in the mitochondria suggests that this pathway, which competes with c-NHEJ in the repair of DSBs, functions within the mitochondria. Indeed, it has been shown that mitochondrial extracts of rat tissues and of HeLa cells that are unable to repair DSBs through c-NHEJ can do so efficiently through MMEJ [150]. Mitochondrial extracts were able to join two dsDNAs with 13-nt microhomologous direct repeats at their ends. The same extracts were unable to join c-NHEJ DNA substrates, demonstrating that MMEJ and not c-NHEJ functions in mtDSBR. Furthermore, immunodepletion of various MMEJ enzymes in the mitochondrial extracts determined that MMEJ in the mitochondria is dependent upon CtIP, FEN1, ligase 3, Mre11, and PARP1, as their immunodepletion caused significant decrease in the efficiency of MMEJ. A majority of mtDNA deletions have also been shown to be flanked by 13-bp direct repeats, thus suggesting that DSBs in the mtDNA are repaired by this mutagenic subpathway [159]. A recent report also documented MMEJ in Arabidopsis mitochondria, dependent on the DNA polymerases AtPolIA and AtPolIB [160]. Further studies are necessary to determine the mechanism and other enzymes possibly involved in MMEJ of the mtDNA.

7.2 Homologous recombination Unlike the error-prone NHEJ pathway, HR has a high degree of fidelity, as the repair machinery uses the homologous DNA sequence from a sister chromatid as a template to repair the damaged DNA. In the nucleus, this is limited to the S and G2 phases of the cell cycle, when a fully replicated sister chromatid is available. This, however, would not impose a limitation in mitochondria, because multiple copies of the mtDNA are generally present at any given time. In fact, it was shown that mitochondrial nucleoids are constantly attaching and detaching from one another, and though they do not exchange protein content, there is no evidence that indicates that they do not exchange genetic information [161].

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Due to the biparental inheritance of mitochondrial DNA in Saccharomyces cerevisiae, detection of mtDNA recombination has been documented more thoroughly [162,163]. In higher eukaryotes, such as humans, where mtDNA is maternally inherited, detecting recombinant mtDNA molecules is difficult, as recombination events between the homologous molecules would give rise to indistinguishable copies of the mtDNA. Some rare cases of paternal inheritance in humans [164,165] and the detection of recombination intermediates in human heart mtDNA by electron microscopy, such as branched structures, and abundant four-way junctions [166,167] have provided the best evidence for recombination of mammalian mtDNA so far, suggesting that homologous recombination machinery is present in mitochondria from all taxa. In yeast mitochondria, many enzymes and proteins involved in the HR machinery have been discovered and studied. Priming and resection of DSB ends are initially performed by endo/exonucleases such as Nuc1, Din7, Exo5, and Rad27p, all of which have been localized in the yeast mitochondria [168,169]. Mgm101, a Rad52-like protein, is named for its function, mitochondrial genome maintenance, and is required for homologous recombination of yeast mtDNA [170]. Mhr1, which participates in yeast mtDNA replication has a necessary role in the pairing of homologous strands for recombination [171]. Yeast mitochondria also have a Holliday junction endonuclease, Cce1, which functions as the resolvase, completing the last enzymatic step in the HR pathway [172]. Less is known regarding homologous recombination in mammalian mitochondria. The initial DSB recognition and end-resection priming step of HR involves the MRN-CtIP complex, which also functions in MMEJ and was discussed earlier. In the nucleus, the MRN complex interacts with BRCA1 to promote end resection. BRCA1 has been shown not only to localize within mitochondria, but to colocalize with mtDNA nucleoids, possibly functioning in HR-mediated repair [173]. In addition to BRCA1, Rad51, which is required for the homologous pairing step of HR, has also been found in mitochondria from human cells [174], and translocates to mitochondria upon replication stress [175]. Rad51 binding to mtDNA was induced by oxidative stress, suggesting a role in repair of oxidatively induced damage. Furthermore, mitochondrial extracts of rat tissues and HeLa cells were able to successfully carry out HR-mediated repair in vitro [176]. Though experimental evidence suggests that both homology-dependent and -independent repair of DSBs may function in mitochondria, further studies are needed to illustrate fully the mechanisms and to determine the mechanistic details involved.

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Acknowledgments This work was supported by Fundac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo (FAPESP) grant 2017/04372-0 and Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo´gico (CNPq) grant 309157/2018-8 to N.C.S-P. R.R.A. is supported by FAPESP grant 2018/04443-8 and CMPFB is supported by CNPq grant 140207/2018-0.

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