Interaction between DNA damage response and autophagy in colorectal cancer

Journal Pre-proofs Review Interaction between DNA damage response and autophagy in colorectal cancer Elmira Roshani Asl, Behzad Mansori, Ali Mohammadi, Souzan Najafi, Fahima Danesh Pouya, Yousef Rasmi PII: DOI: Reference:

S0378-1119(19)30982-5 https://doi.org/10.1016/j.gene.2019.144323 GENE 144323

To appear in:

Gene Gene

Received Date: Revised Date: Accepted Date:

23 August 2019 21 December 2019 30 December 2019

Please cite this article as: E. Roshani Asl, B. Mansori, A. Mohammadi, S. Najafi, F. Danesh Pouya, Y. Rasmi, Interaction between DNA damage response and autophagy in colorectal cancer, Gene Gene (2020), doi: https:// doi.org/10.1016/j.gene.2019.144323

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Interaction between DNA damage response and autophagy in colorectal cancer Elmira Roshani Asl1,2, Behzad Mansori2,3,4, Ali Mohammadi3, Souzan Najafi2, Fahima Danesh Pouya1,Yousef Rasmi1,5 1Department

of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran

2Immunology 3Department

Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

of Cancer and Inflammation Research, Institute for Molecular Medicine, University

of Southern Denmark, Odense, Denmark 4

Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.

5Cellular

and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran

*Corresponding Author: Dr. Yousef Rasmi, Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran. tel: +984432770698, fax: +984432780801, E-mail: [email protected]

Interaction between DNA damage response and autophagy in colorectal cancer Elmira Roshani Asl1,2, Behzad Mansori2,3,4, Ali Mohammadi3, Souzan Najafi2, Fahima Danesh Pouya1,Yousef Rasmi1,5 1Department

of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran

2Immunology 3Department

Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

of Cancer and Inflammation Research, Institute for Molecular Medicine, University

of Southern Denmark, Odense, Denmark 4

Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.

5Cellular

and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran

*Corresponding Author: Dr. Yousef Rasmi, Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran. tel: +984432770698, fax: +984432780801, E-mail: [email protected]

Highlights 

Accumulation of DNA damage leads to the progression of cancer in more metastatic and invasive forms.



DNA damage response (DDR) plays a central role in maintaining genome integrity.



Autophagy, which is a physiological self-eating, has been demonstrated to be involved in DNA damage.



The interplay between DDR and autophagy may have a critical role in the pathogenesis of various malignancies.

Abstract The subjection of DNA to numerous lethal damages is threatening for the stability and integrity of the whole body genome. DNA damage response (DDR) is a critical phosphorylation-based signaling pathway developed for the maintaining of the genome against these threatens. Recent studies showed that various targets of DDR are involved in the activation of autophagy, as one of the important effectors of this signaling. The interplay between DDR and autophagy may have a critical role in the pathogenesis of various malignancies such as colorectal cancer, which can be a basement for the designing novel therapeutic strategies for combating this

cancer type. On the other hand, autophagy is also demonstrated to be contributed tothe regulation of DDR components. Therefore, in this review article, we will discuss the crosstalk between DDR and autophagy and their exact function in the pathogenesis of various human cancer types, with special attention on colorectal cancer. Keywords: DNA damage, DNA repair, Autophagy, Colorectal cancer

Introduction Colorectal cancer is accounted for among the most common malignancies in both women and men and its incidence rate is highly increasing every year, worldwide (Siegel et al., 2017). Despite a huge focus in developing more effective therapeutic and screening strategies, colorectal cancer still remains a major life-threatening malignancy (Siegel et al., 2017; ten Hoorn et al., 2018). Colorectal cancer normally begins from benign lesions and accumulation of DNA damage leads to the progression of cancer to more metastatic and invasive forms(Dienstmann et al., 2017). Since early detection of the lesions enables the clinician to pause cancer progression, screening programs have undeniable value in preventing transformation to malignant lesions (Winawer et al., 2003; Beggs and Hodgson, 2008). On the other hand, designing novel therapeutic strategies with appropriate effectiveness needs clear elucidation of molecular mechanisms involved in the initiation and progression of this lethal malignancy. For this reason, an accumulating body of recent studies focuses on DNA damage response (DDR), and its possible role in the development of colorectal cancer (Collins and Hurwitz, 2005; Gilbert et al., 2012). On the other hand, recent studies have been demonstrated that interplay between DDR and autophagy may have a critical role in the pathogenesis of various malignancies such as colorectal cancer, which can be a basement for the designing novel therapeutic strategies for combating this cancer type (Rodriguez-Rocha et al., 2011; Czarny et al., 2015). Therefore, the main scope of this review is discussing the function of autophagy in colorectal cancer initiation/progression, as well as the importance of crosstalk between DDR and autophagy in colorectal cancer.

DNA damage response Every day, each cell within the body is subjected to tens of thousands of DNA damages, lack of an appropriate system to respond and delete of whom results in the disruption in the maintaining of integrity and stability of the whole genome and consequence development of various life-threatening diseases such as cancer(Blackford and Jackson, 2017). Some important DNA lesions include single-strand breaks (SSB), double-strand breaks (DSB), pyrimidine dimers, photoproducts, covalent crosslinks between DNA bases, and attachment of alkyl groups to bases, which are induced by numerous genetic and environmental factors such as ionizing radiation (IR), ultraviolet (UV) light, and chemotherapeutics (8). DDR is an intricate kinase-based signaling pathway, which senses, transduces, and exerts a strong effect on any DNA lesions(Natale et al., 2017; Ogawa and Baserga, 2017). Therefore, the main players of this network are comprised of sensors, which sense and detect DNA damage and include MRE11/RAD50/NBS1 (MRN) complex for detection of DSB and RAD9/RAD1/HUS1 (9-1-1) for sensing SSB, transducers, which transduce the damage signal from sensors to effectors and include Ataxia telangiectasia mutated (ATM) and ATM and RAD3-related (ATR),as well as by two downstream kinases, checkpoint kinases 1 and 2(Chk1 and Chk2) and finally effectors(p53 and BRCA2), which decide cell fate between three major effects: cell cycle arrest, DNA repair and apoptosis (Khamis, 2017; Mouw et al., 2017) (Fig.1). In order to maintain the genome health, DDR machinery does not function alone, but rather coordinates with other various complementary machines such as chromatin-remodeling mechanism, to provide the accessibility of the DNA repair components to the DNA damages site within

chromosomes, homologous recombination, chromosome cohesion machinery, cell-cycle-checkpoint and chromosome-segregation machinery(Mateo and de Bono, 2017). The whole process of the DDR pathway takes place before the cell enters the mitotic phase to

ensure the passing of the correct complement of genetic material to daughter cells(Soria-Valles et al., 2017).

Autophagy Autophagy (a Greek word that means self-eating) that was originally proposed by Christian de Duve more than 40 years ago, is a ubiquitous highly conserved catabolic pathway involved in the removal and digestion of excessive, dysfunctional or long-lived proteins, cellular constituents, as well as organelles(De Duve and Wattiaux, 1966; Lane et al., 2017). Autophagy is broadly classified into macroautophagy, microautophagy and chaperone-mediated autophagy (CMA), and the term of autophagy usually indicate macroautophagy(Eskelinen and Saftig, 2009; Wen and Klionsky, 2016) (Fig. 2).Autophagy is mediated by a special organelle termed the autophagosome(Mizushima, 2007).This pathway is responsible for the maintenance of the hemostasis in normal physiological conditions, however, some special conditions such as hypoxia, DNA damage, nutrition starvation, and oxidative stress result in the potent induction of autophagy(Lane et al., 2017). More importantly, autophagy has a critical function in a broad range of pathological processes, some important examples of them include, aging, development of the placenta, adaptive response to starvation, antigen presentation, genomic stability and tumorigenesis(Fulda, 2017). The importance of this pathway is such great that its dysregulation is contributed tothe development of neurodegenerative disease, cardiovascular disorders, and cancer(Yorimitsu and Klionsky, 2005). In

addition, in the determination of cell fate, autophagy is suggested to act as a double-edged sword because of condition-dependent activation of survival pathways or programmed cell death. Autophagy is initiated by the formation of autophagosome complex by autophagy-related genes (ATGs)(Yorimitsu and Klionsky, 2005). Approximately, thirty-six ATGs have been recognized and characterized until now. An UNC-51-like kinase (ULK) consisted of ULK1, ATG13, ATG101 and RB1CC1/FIP200 (RB1-inducible coiled-coil 1), and class III phosphatidylinositol 3-kinase (PI3K) complexes are involved in the initiation of the autophagosome formation(Mokarram et al., 2017). After that, class III phosphatidylinositol 3-kinase (PtdIns3K) complex binding to its core units, including BECN1/Beclin-1 and PIK3R4/p150, results in the arising of complex nucleation(Yorimitsu and Klionsky, 2005; Mokarram et al., 2017). This complex settles to the phagophore membrane and facilitates the recruitment of other ATGs to the units(Klionsky, 2009; Yang and Klionsky, 2010). In the phagophore maturation and elongation phase, the ATG8/LC3 protein conjugation with membrane lipid phosphatidylethanolamine (PE) or phosphatidylserine is occurred(Hippert et al., 2006) (Fig. 3). ATG8 family of ubiquitin-like proteins is consisted of two subfamilies including MAP1LC3B/ LC3(microtubule-associated protein 1 light chain 3 B), which is consisted of LC3A, B, B2 and C, and GABARAP (gamma-aminobutyric acid receptor-associated protein), which consisted of GABARAP, GABARAPL1 and GATE-16(also known as GABARAPL2)(Yang and Klionsky, 2010). Following the cleavage of precursor protein by cysteine protease ATG4B, LC3-I and LC3-II, and GABARAP-I and GABARAP-II receive the nonlipidated and lipidated forms, respectively(Mizushima et al., 2008). An important analytical marker of autophagic flux is an enhanced level of LC3II in the presence of lysosomal proteases inhibitors. In the final phase of autophagy, lysosomal hydrolases degrade cargo in the autolysosomes and the resulting products are transported back to the cytosol by lysosomalpermeases(Burada et al., 2015).

Figure 2.Classification of autophagy. There are several different classifications of autophagy such as macroautophagy, microautophagy, chaperone-mediated autophagy (CMA). LAMP2-A:lysosome-associated membrane protein type 2A.

Figure 3.Molecular components of autophagosome formation.Pro-autophagic signals such as nutrient or energy depletion, hypoxia activate regulatory components of the autophagic machinery, such as the ULK1 and Beclin-1 complexes. ULK1: unc51-like autophagy activating kinase 1; Beclin-1: a protein that in humans is encoded by the BECN1 gene; PI3K: class III phosphatidylinositol 3-kinase; LC3: microtubule-associated protein 1A/1B-light chain 3.

DDR and autophagy crosstalk in cancer As mentioned before, autophagy plays a dual and contradictory function in tumorigenesis. In normal cells, autophagy acts as a surveillance pathway by clearance aggregated and misfoldedproteins, removing damaged organelles, as well as decreasing DNA lesions, free radicals, and mitochondrial abnormalities in order to cellular protection from malignant transformations(Choi et al., 2013). On the other hand, autophagy is involved in the supplying of nutrients required for the metabolism and growth of malignant cells, suppressing cellular death and developing multidrug resistance, all of which resulted in the hypothesis that autophagy supports tumorigenesis(Galluzzi et al., 2015). During the metastatic phase of cancer, cell response to autophagy is stage-dependent such that it can promote inflammatory response against cancer cells, hence reduce decrease tumor cell dissemination and consequent cancer metastasis in early stages(Kenific et al., 2010; Panda et al., 2015). In addition, tumor necrosis and expansion of dormant tumor cells into micrometastases can also be limited by autophagy. However, during advanced stages of metastasis, autophagy enhances the survival of detached metastatic cells in the absence of extracellular matrix, and support metastasis(Su et al., 2015). Autophagy is

extensively demonstrated to be regulated by a broad range of signaling pathways. The mammalian target of rapamycin (mTOR) is one of the most important regulators of autophagy. mTOR, itself is under-regulation of the class I phosphoinositide 3- kinase/Akt (PI3K/Akt), which potently down-regulates autophagy(Esclatine et al., 2009; He and Klionsky, 2009). Moreover, LKB1(liver kinase B1), TAK1(transforming growth factor β-activated protein kinase-1), and CaMKKb(calcium-calmodulin kinase kinase-2), are the upstream effectors of adenosine monophosphate-activated protein kinase (AMPK), which activate thiskinase. AMPK also modulates mTOR in a negative manner by two mechanisms, suppression of mTOR and stimulation of tuberous sclerosis 2 (TSC2) proteins, all of which results in autophagy induction(Yang and Klionsky, 2010; Li et al., 2012) (Fig. 4). More importantly, an accumulating body of recent studies hasbeen suggested that DNA damage and DNA repair play a critical function in the regulation of autophagy(Klionsky and Emr, 2000; Polager et al., 2008). ATM, as one of the substantial factors involved in the transducing of the DNA damage signal, is activated by MRN complex, and following the recruitment to the damage site, its autophosphorylation and releasing from its inactive dimmer state results in the phosphorylation of various downstream targets in order to exert an appropriate response to DNA damage(Czarny et al., 2015). Some studies have demonstrated that ATM activation results in the suppression of mTOR signaling through the AMPK pathway and finally activates the autophagy system. Depending on the cell conditions and the severity of DNA lesions, with regard to reparable or irreparable lesions, different cellular fate can be triggered(Eliopoulos et al., 2016). P53, a key effector of DDR with a central role in determining cell fate, has a bidirectional function in the modulation of autophagy depending on its subcellular localization. p53 can either induce AMPK, which inactivates mTOR hence activating autophagy, or increase the transcriptional expression of damage-regulated autophagy modulator (DRAM), which is a lysosomal protein that facilitates the

autophagic process(Crighton et al., 2006; Crighton et al., 2007). Moreover, p53 is also able to suppress mTOR through activation of PTEN (Phosphatase and tensin homolog), a potent suppressor of the PI3K/Akt pathway, therefore, induce autophagy. In contrast to nuclear p53, cytoplasmic p53 acts as an inhibitor of autophagy(Maiuri et al., 2010) (Fig. 5). In addition, recent studies reported that tumor cells represent an increased level of autophagy and DNA repair, in comparison with normal cells(Gomes et al., 2017). Additionally, autophagy and DNA repair act in harmony with each other in order to affect tumor development and in controlling the response to chemotherapy and/or radiation(Nazio et al., 2018). Therefore, understanding the relationship between autophagy and DNA repair may allow us to develop a promising therapeutic strategy to increase the present efficacy of anticancer therapy and improve clinical outcomes.

Figure 4.AMPK and mTOR signaling network.Nutrients and growth factors regulate the mTORC1 complex in mammalian cells. CAMKKβ: calcium/calmodulin-dependent protein kinase kinase-β; LKB1: liver kinase B1; TAK1: transforming growth factor β-activated protein kinase-1; AKT: also known as protein kinase B; TSC2: tuberous sclerosis complex 2; AMPK: adenosine monophosphate-activated protein kinase; MTORC1: mammalian target of rapamycin complex 1.

Figure 5. DNA damage mediated induction of autophagy. Cytoplasmic p53 has been shown to repress autophagy and nuclear translocation of p53 stimulates autophagy. ATM: ataxia telangiectasia mutated; ATR: ATM and RAD3-related; P53: tumor protein p53; TSC: tuberous sclerosis;mTOR: mammalian target of rapamycin; DRAM: damage-regulated autophagy modulator; PTEN: Phosphatase and tensin homolog;PI3K: class III phosphatidylinositol 3-kinase; AKT: also known as Protein kinase B

DDR and autophagy crosstalk in colorectal cancer Autophagy is reported to have a critical function in colorectal cancer progression. Some important players of autophagy are extensively demonstrated to be contributed in the switch from normal to malignant colorectal tissue (Zhou et al., 2016; Mokarram et al., 2017; Qian et al., 2017). A comprehensive list of these genes is discussed in table 1. As mentioned before, autophagy is subjected to be regulated by various key targets of DDR, which may have a critical role in the pathogenesis of various signaling pathways. Recent studies have been demonstrated that there is a dual interrelationship between DDR and autophagy, which is involved in colorectal cancer. For example, Seiwert et al.(Seiwert et al., 2017) reported that colorectal cancer cell lines treatedwith IR resulted in a significant increase in autophagy. Silencing of p53 and suppression of ATM signaling also led to impair the autophagic flux as observed by LC3B-II accumulation and decreased the formation of the autophagic vesicle. The authors showed that DSBs induced by IR trigger pro-survival autophagy in an ATM- and p53-dependent manner, which is curtailed by AKT2 signaling (Seiwert et al., 2017). More importantly, various therapeutic agents exert their beneficial anti-colorectal cancer effects through autophagy-mediated induction in the DDR signaling pathway. Mao et al. (Mao et al., 2017) showed that Ku-0060648, a novel inhibitor of both PI3K-AKTmTOR cascade and DNA-PKcs, efficiently suppressed cancer cells proliferation and induced apoptosis in HCT-116 colorectal cancer

cell lines. Cell treatment with Ku-0060648 treatment activated autophagy activation. More importantly, pharmacological inhibition of gene silencing of autophagy potentiated Ku-0060648-induced cell apoptosis. In other words, autophagy activation could lead to the development of resistance to Ku-0060648 in colorectal cancer cell lines (Mao et al., 2017). In another study by Wang et al. (Wang et al., 2018) it was demonstrated that interferon- (IFN-) treatment of SW480 and HCT116 colorectal cancer cell lines resulted in the increased levels of mitochondrial ROS production and induction of autophagy, hence increased the number of apoptotic cells through activation of cytosolic phospholipase A2 (cPLA2). Autophagy suppression through Beclin-1 gene silencing decreased IFN--induced cell apoptosis, as evident by caspase-3 inactivation, decreased Bax/Bcl-2 ratio(Wang et al., 2018). The ginsenoside Rh4 (Rh4), a rare saponin obtained from Panax notoginseng, was reported to successfully inhibit the proliferation of colorectal cancer cells through inducing G0/G1 phase arrest, caspase-dependent apoptosis, and induction of autophagy. This compound was shown to enhance ROS accumulation subsequent activation of the JNK-p53 pathway (Wu et al., 2018). Autophagy is also reported to be involved in the induction of senescence of colorectal cancer cells, as another effector pathway of DDR. In a study by Mosieniak et al.(Mosieniak et al., 2012), it was showed that suppression of autophagy, by decreasing the expression of ATG5 through gene silencing reduced the number of senescent cells induced by Curcumin, but did not lead to enhanced cell death. The authors reported a functional link between senescence and autophagy in Curcumin-treated cells.

Conclusion In this review article, we discussed the crosstalk between autophagy and DDR, and their critical function in the various aspects of cancer pathology, with special attention to colorectal cancer. Autophagy-mediated increase in ROS production and induction in various DDR effector pathways such as apoptosis, cell cycle arrest and senescence are commonly observed in the colorectal cancer cells treatedwith various therapeutic agents. However, the research in the area of the effects of crosstalk between DDR and autophagy on colorectal cancer is still in its infancy. More future investigations need to do for the elucidation of the effects of autophagy on the sensors and transducers of DDR and their function in the pathogenesis of colorectal cancer.

Conflict of Interests Authors have no conflict of interests.

Table 1: autophagy-related genes with a critical function in colorectal cancer genes

Function in autophagy

Function in tumorigenesis

Function in colorectal cancer

Ref.

LC3-II

essential to the formation of

Have prognostic significance

Increased:

(Sato et al.,

autophagosomes

Overexpressed in relevant cancer

expression levels particularly in advanced stages

2007;

types such as lung cancer

expression levels is related to aggressiveness

Giatromanolaki

perinuclear expression levels are related to a positive prognosis

et al., 2010; Li

expression levels in colorectal cell lines treated with autophagy inhibitors

et al., 2010;

expression levels in colorectal cell lines treated with 5-FU and

Guo et al.,

radiotreated, alone or in combination

2011; Zheng et

Decreased:

al., 2012; Chen

expression levels is related to good outcome and treatment

et al., 2013;

response Negative expression associated with poor clinical outcome and survival Beclin-1

Schonewolf et al., 2014; Yang et al., 2015a)

The essential modulator of

Deleted in a relevant fraction of

Increased:

(Zhang et al.,

autophagy

human breast, ovarian and

expression levels is negatively associated with metastasis

2014)(Li et al.,

prostate tumors.

expression levels is related to a favorable outcome

2009; Guo et

Brain tumors are characterized by

expression levels is related to longer survival in patients treated with 5-

al., 2011; Han

reducedexpression of BECN1

FU

et al., 2014;

expression levels is related to worse survival in patients treated with 5-

Yang et al.,

FU

2015a; Yang et

expression levels is related to metastasis and worse prognosis

al., 2015b;

expression levels is related to poor clinical outcome and survival

Zaanan et al., 2015)

Decreased: expression levels is related to increased survival in advanced patients treated with cetuximab

expression levels is related to a good response after chemoradiation in patients with rectal cancer

ATG5

functions as an E1-like

Prognostic marker in renal cancer

Increased:

(An et al.,

activating enzyme in a

(unfavorable) and liver cancer

expression levels is related to lymphovascular invasion

2011; Cho et

ubiquitin-like conjugating

(unfavorable).

system

Most of the cancer tissues showed moderate cytoplasmic positivity. A

decreased: expression levels in colorectal cancer expression levels is related to poor clinical outcome survival

few liver cancers were strongly stained. Lymphomas and gliomas

al., 2012; Selvakumaran et al., 2013; Choi et al.,

expression levels increased sensitivity to oxaliplatin

2014)

were weakly stained or negative.

ATG10

is an E2-like enzyme

Prognostic marker in liver cancer

Increased:

(Jo et al.,

involved in 2 ubiquitin-like

(unfavorable).

expression levels is related to tumor lymph node metastasis and poor

2012)

modifications

Cancer tissues showed weak to

survival

moderate membranous and/or cytoplasmic staining. Gliomas were mostlynegative.

ATG16L1

interacts with ATG12-ATG5

Prognostic marker in liver cancer

ATG16L1T300A polymorphism improved overall survival in human

to mediate the conjugation of

(unfavorable) and renal cancer

CRC patients

phosphatidylethanolamine

(unfavorable).

(Grimm et

(PE) to LC3

Most cancer tissues showed weak to

al., 2016)

moderate cytoplasmic and membranous immunoreactivity for it.

Bcl-2

Negative regulator of

Overexpressed in a relevant

Increased :

(Koehler et

autophagy by sequestering

proportion of human cancers, and

expression levels is related to migration and invasion

al., 2013; Wu

BECN1

notably in hematological

expression levels is related to resistance to paclitaxel

et al., 2013)

malignancies

Bif-1

Interacts with Beclin-1 and

Inhibits cancer cells proliferation,

Decreased

(Coppola et

regulates autophagy

survival, and migration

in colorectal cancer

al., 2008)

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Abbreviation AMPK: Adenosine monophosphate-activated protein kinase, ATGs: autophagy-related genes, ATM: Ataxia telangiectasia mutated, CaMKKb: Calcium-calmodulin kinase kinase-2, Chk1: checkpoint kinases 1, Chk2: checkpoint kinases 2, CMA: Chaperone-mediated autophagy, cPLA2: Cytosolic phospholipase A2, DDR: DNA damage response, DRAM: Damage-regulated autophagy modulator, DSB: Double strand breaks, IFN-: Interferon-, IR: Ionizing radiation, LKB1: liver kinase B1, MRN: MRE11/RAD50/NBS1, mTOR: Mammalian target of rapamycin, PE: Phosphatidylethanolamine, PI3K/Akt: Class I phosphoinositide 3- kinase/Akt, PTEN: Phosphatase and tensin homolog, RB1CC1/FIP200: RB1-inducible coiled-coil 1, SSB: Singlestrand breaks, TAK1: Transforming growth factor-β activated protein kinase-1, TSC2: Tuberous sclerosis 2, ULK: UNC-51-like kinase, UV: Ultraviolet,

Abstract The subjection of DNA to numerous lethal damages is threatening for the stability and integrity of the whole body genome. DNA damage response (DDR) is a critical phosphorylation-based signaling pathway developed for the maintaining of the genome against these threatens. Recent studies showed that various targets of DDR are involved in the activation of autophagy, as one of the important effectors of this signaling. The interplay between DDR and autophagy may have a critical role in the pathogenesis of various malignancies such as colorectal cancer, which can be a basement for the designing novel therapeutic strategies for combating this cancer type. On the other hand, autophagy is also demonstrated to be contributed to the regulation of DDR components. Therefore, in this review article, we will discuss the crosstalk between DDR and autophagy and their exact function in the pathogenesis of various human cancer types, with special attention on colorectal cancer.

Keywords: DNA damage, DNA repair, Autophagy, Colorectal cancer

Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Highlights 

Accumulation of DNA damage leads to the progression of cancer in more metastatic and invasive forms.

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DNA damage response (DDR) plays a central role in maintaining genome integrity.

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Autophagy, which is a physiological self-eating, has been demonstrated to be involved in DNA damage.

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The interplay between DDR and autophagy may have a critical role in the pathogenesis of various malignancies.