- Email: [email protected]
A break is not the End; insight into the damage response to DNA double strand breaks
DNA Repair 9 (2010) 1217–1218
Contents lists available at ScienceDirect
DNA Repair journal homepage: www.elsevier.com/locate/dnarepair
Preface
A break is not the End; insight into the damage response to DNA double strand breaks
DNA double strand breaks (DSBs) are critical lesions underlying genomic instability, yet they are generated on a daily basis in many of our cells with no deleterious outcome – such is the efficacy of the DNA damage response. However, during the aetiology of carcinogenesis, tumour cells ‘molest’ the protective mechanisms; more DSBs are generated and the DNA damage response is defiantly corrupted to merge genomic instability with enhanced proliferative capacity. In this DNAR Special Issue entitled “A break is not the End; insight into the damage response to DNA double strand breaks”, we overview current thoughts and knowledge on how the DSB responses function at the structural, molecular and cellular level and how these processes change in cancer cells. In 2004, Yossi Shiloh edited one of the first DNAR Special Issues entitled “Bridge over Broken Ends; the cellular response to DNA Breaks in Health and Disease”. This was a seminal issue of DNAR, written at a time when sensors, mediators and transducers in the signalling response were being identified and their roles dissected. The distinct mechanisms of repair and signalling following DSB induction by exogenous damage and programmed processes were appreciated and underwent close examination. So much ground has been traversed in the intervening years that the time seems right for a fresh look at the subject. In a more focused Special Issue than its forerunner, we cover solely responses to DSBs and encompass topical and fast moving areas in this dynamic field. Journals now place such tight size constraints that there is little scope for model building or thought projection in original research articles. Here, we aim to allow leaders in the field to integrate distinct findings, discuss models and present novel, or indeed provocative, ideas in a way that can seldomly be achieved in primary research papers. The response to DSBs encompasses pathways of DSB repair and a signal transduction process that activates a range of endpoints including cell cycle checkpoint arrest and apoptosis. Recent studies have demonstrated close interplay between these processes and shown that they function in a regulated, co-ordinated manner with the signalling response monitoring the progress of DSB repair and DSB repair being strongly influenced by the signalling response. Thus, although the first few articles focus on the signalling response and following ones on repair, there is close overlap – indeed this closely interwoven network is a theme evident in nearly all articles. Perhaps the greatest advance in recent years has been unravelling the exquisite choreography of proteins that assemble at DSB sites generating irradiation induced foci (IRIF). This work has encompassed the identification of new players in the damage response team and understanding their ordered assembly. Partly as a consequence of this work but aided by additional 1568-7864/$ – see front matter © 2010 Published by Elsevier B.V. doi:10.1016/j.dnarep.2010.09.021
studies, the significance of post-translational modifications, including phosphorylation, ubiquitylation, sumoylation, methylation and acetylation, in modifying the chromatin structure in the vicinity of the DSB is emerging. Indeed, a significant advance of recent years is the recognition that a critical function of ATM is the modulation of the chromatin environment around a DSB. The first two articles in this issue cover these exciting advances, over-viewing our current understanding of the assembly of IRIF (Bekker-Jensen and Mailand) and the function of ubiquitin modifications in the damage response (Al-Hakim et al.). Liu et al. review their recent findings showing that RAD18 is a further protein that accumulates at IRIF but has distinct functions, with a direct role in homologous recombination (HR) and a distinct role as a ubiquitin ligase. Although ATM is often considered to be the protein kinase of central significance to the DSB damage response, ATR plays a critical function at the replication fork where both DSBs and single strand breaks can arise. The fourth article (Lopez-Contreras and Fernandez-Capetillo) overviews the dynamic relationship between ATR, ageing and cancer. Subsequent articles focus more on the DSB repair processes, providing insight into the interplay or steps in DNA non-homologous endjoining and microhomology mediated end-joining (Hiom) or HR (Holthausen et al.). The impact of higher order chromatin structure on DSB repair processes adds to the emerging recognition of the importance of chromatin structure to the damage response (Goodarzi et al.). The regulation of DSB end-resection represents another area of fast moving research and recent advances in the complex interplay of nucleases that appropriately promote resection is covered by Paull. DNA damage responses have been well conserved during evolution, allowing us to benefit from specific model organisms that each provides their own benefit. The article by Evans et al. discusses the benefits of chicken cells for a genetics based high throughput analysis. Finally, recent years have seen our understanding of protein structure progress by leaps and bounds. Such analysis provides an important interface with cellular analysis to deduce how a protein or protein complex functions and is invaluable for drug targeting purposes. The studies on the Mre11-Rad50-NBS1 (MRN) complex have been ground breaking in this context and the role of MRN in sensing and processing DSBs is overviewed by Williams et al. The enormous size of the protein kinases involved in damage response signalling has restricted structural studies. Undaunted by the enormous size of the DNA-PK catalytic subunit (DNA-PKcs), Dobbs et al. describe the range of techniques used to gain structural information that is shaping the way we think about DNA-PK function and indeed, the other damage response kinases. In summary, this selection of
1218
Preface / DNA Repair 9 (2010) 1217–1218
reviews covers topical areas in our rapidly advancing field and, more importantly, encompasses new models and concepts. I would like to thank Errol Friedberg for enabling me to edit this special issue and bring to the forefront this exciting area of research. I also wish to thank Theresa West for gentle prompting, help and advice. Finally, I thank all the authors who have given their time and thoughts to writing such excellent reviews, which were (mostly) completed in a timely manner. I hope that “A Break is not the End” will be enjoyable and informative reading for many.
Penny A. Jeggo ∗ Genome Damage and Stability Centre, University of Sussex, Brighton, East Sussex BN1 9RQ, United Kingdom ∗ Tel.:
+44 1273 678482; fax: +44 1273 678121. E-mail address: [email protected] Available online 16 October 2010
Contents lists available at ScienceDirect
DNA Repair journal homepage: www.elsevier.com/locate/dnarepair
Preface
A break is not the End; insight into the damage response to DNA double strand breaks
DNA double strand breaks (DSBs) are critical lesions underlying genomic instability, yet they are generated on a daily basis in many of our cells with no deleterious outcome – such is the efficacy of the DNA damage response. However, during the aetiology of carcinogenesis, tumour cells ‘molest’ the protective mechanisms; more DSBs are generated and the DNA damage response is defiantly corrupted to merge genomic instability with enhanced proliferative capacity. In this DNAR Special Issue entitled “A break is not the End; insight into the damage response to DNA double strand breaks”, we overview current thoughts and knowledge on how the DSB responses function at the structural, molecular and cellular level and how these processes change in cancer cells. In 2004, Yossi Shiloh edited one of the first DNAR Special Issues entitled “Bridge over Broken Ends; the cellular response to DNA Breaks in Health and Disease”. This was a seminal issue of DNAR, written at a time when sensors, mediators and transducers in the signalling response were being identified and their roles dissected. The distinct mechanisms of repair and signalling following DSB induction by exogenous damage and programmed processes were appreciated and underwent close examination. So much ground has been traversed in the intervening years that the time seems right for a fresh look at the subject. In a more focused Special Issue than its forerunner, we cover solely responses to DSBs and encompass topical and fast moving areas in this dynamic field. Journals now place such tight size constraints that there is little scope for model building or thought projection in original research articles. Here, we aim to allow leaders in the field to integrate distinct findings, discuss models and present novel, or indeed provocative, ideas in a way that can seldomly be achieved in primary research papers. The response to DSBs encompasses pathways of DSB repair and a signal transduction process that activates a range of endpoints including cell cycle checkpoint arrest and apoptosis. Recent studies have demonstrated close interplay between these processes and shown that they function in a regulated, co-ordinated manner with the signalling response monitoring the progress of DSB repair and DSB repair being strongly influenced by the signalling response. Thus, although the first few articles focus on the signalling response and following ones on repair, there is close overlap – indeed this closely interwoven network is a theme evident in nearly all articles. Perhaps the greatest advance in recent years has been unravelling the exquisite choreography of proteins that assemble at DSB sites generating irradiation induced foci (IRIF). This work has encompassed the identification of new players in the damage response team and understanding their ordered assembly. Partly as a consequence of this work but aided by additional 1568-7864/$ – see front matter © 2010 Published by Elsevier B.V. doi:10.1016/j.dnarep.2010.09.021
studies, the significance of post-translational modifications, including phosphorylation, ubiquitylation, sumoylation, methylation and acetylation, in modifying the chromatin structure in the vicinity of the DSB is emerging. Indeed, a significant advance of recent years is the recognition that a critical function of ATM is the modulation of the chromatin environment around a DSB. The first two articles in this issue cover these exciting advances, over-viewing our current understanding of the assembly of IRIF (Bekker-Jensen and Mailand) and the function of ubiquitin modifications in the damage response (Al-Hakim et al.). Liu et al. review their recent findings showing that RAD18 is a further protein that accumulates at IRIF but has distinct functions, with a direct role in homologous recombination (HR) and a distinct role as a ubiquitin ligase. Although ATM is often considered to be the protein kinase of central significance to the DSB damage response, ATR plays a critical function at the replication fork where both DSBs and single strand breaks can arise. The fourth article (Lopez-Contreras and Fernandez-Capetillo) overviews the dynamic relationship between ATR, ageing and cancer. Subsequent articles focus more on the DSB repair processes, providing insight into the interplay or steps in DNA non-homologous endjoining and microhomology mediated end-joining (Hiom) or HR (Holthausen et al.). The impact of higher order chromatin structure on DSB repair processes adds to the emerging recognition of the importance of chromatin structure to the damage response (Goodarzi et al.). The regulation of DSB end-resection represents another area of fast moving research and recent advances in the complex interplay of nucleases that appropriately promote resection is covered by Paull. DNA damage responses have been well conserved during evolution, allowing us to benefit from specific model organisms that each provides their own benefit. The article by Evans et al. discusses the benefits of chicken cells for a genetics based high throughput analysis. Finally, recent years have seen our understanding of protein structure progress by leaps and bounds. Such analysis provides an important interface with cellular analysis to deduce how a protein or protein complex functions and is invaluable for drug targeting purposes. The studies on the Mre11-Rad50-NBS1 (MRN) complex have been ground breaking in this context and the role of MRN in sensing and processing DSBs is overviewed by Williams et al. The enormous size of the protein kinases involved in damage response signalling has restricted structural studies. Undaunted by the enormous size of the DNA-PK catalytic subunit (DNA-PKcs), Dobbs et al. describe the range of techniques used to gain structural information that is shaping the way we think about DNA-PK function and indeed, the other damage response kinases. In summary, this selection of
1218
Preface / DNA Repair 9 (2010) 1217–1218
reviews covers topical areas in our rapidly advancing field and, more importantly, encompasses new models and concepts. I would like to thank Errol Friedberg for enabling me to edit this special issue and bring to the forefront this exciting area of research. I also wish to thank Theresa West for gentle prompting, help and advice. Finally, I thank all the authors who have given their time and thoughts to writing such excellent reviews, which were (mostly) completed in a timely manner. I hope that “A Break is not the End” will be enjoyable and informative reading for many.
Penny A. Jeggo ∗ Genome Damage and Stability Centre, University of Sussex, Brighton, East Sussex BN1 9RQ, United Kingdom ∗ Tel.:
+44 1273 678482; fax: +44 1273 678121. E-mail address: [email protected] Available online 16 October 2010