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In eukaryotes, detection and repair of DNA double-strand breaks (DSBs) operate within chromatin, an incredibly complex structure that tightly packages and regulates DNA metabolism. Chromatin participates in the repair of these lesions at multiple steps, from detection to genomic sequence recovery and chromatin is itself extensively modified during the repair process. In recent years, new methodologies and dedicated techniques have expanded the experimental toolbox, opening up a new era granting the high-resolution analysis of chromatin modifications at annotated DSBs in a genome-wide manner. A complex picture is starting to emerge whereby chromatin is altered at various scales around DSBs, in a manner that relates to the repair pathway used, hence defining a 'repair histone code'. Here, we review the recent advances regarding our knowledge of the chromatin landscape induced in cis around DSBs, with an emphasis on histone post-translational modifications and histone variants. Highlights The development of specialized tools has recently provided unprecedented insights regarding the role of chromatin structure in the response to DNA double-strand breaks. High-resolution studies revealed that chromatin is modified on several different scales following DSB induction, ranging from a few kilobases to several megabases. Chromatin modifications at the megabase level may alter the physical properties of the chromatin fiber and regulate long-range chromosomal mobility upon damage. The nature and extent of local chromatin modifications are different upon repair by NHEJ or HR. Repair pathway-specific modifications have the potential to regulate the access of repair factors and the physical properties of the nucleosome, thereby participating in downstream repair events. [ABSTRACT FROM AUTHOR]

Ataxia Telangiectasia Mutated (ATM) has been known for decades as the main kinase mediating the DNA Double-Strand Break Response (DDR). Extensive studies have revealed its dual role in locally promoting detection and repair of DSBs as well as in activating global DNA damage checkpoints. However, recent studies pinpoint additional unanticipated functions for ATM in modifying both the local chromatin landscape and the global chromosome organization, more particularly at persistent breaks. Given the emergence of a novel and unexpected class of DSBs prevalently arising in transcriptionally active genes and intrinsically difficult to repair, a specific role of ATM at refractory DSBs could be an important and so far overlooked feature of Ataxia Telangiectasia (A-T) a severe disorder associated with ATM mutations. [ABSTRACT FROM AUTHOR]

Summary DNA double-strand breaks (DSBs) elicit the so-called DNA damage response (DDR), largely relying on ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PKcs), two members of the PI3K-like kinase family, whose respective functions during the sequential steps of the DDR remains controversial. Using the DIvA system (DSB inducible via Asi SI) combined with high-resolution mapping and advanced microscopy, we uncovered that both ATM and DNA-PKcs spread in cis on a confined region surrounding DSBs, independently of the pathway used for repair. However, once recruited, these kinases exhibit non-overlapping functions on end joining and γH2AX domain establishment. More specifically, we found that ATM is required to ensure the association of multiple DSBs within “repair foci.” Our results suggest that ATM acts not only on chromatin marks but also on higher-order chromatin organization to ensure repair accuracy and survival. [ABSTRACT FROM AUTHOR]

We have identified a novel evolutionarily conserved protein motif – designated the THAP domain – that defines a new family of cellular factors. We have found that the THAP domain presents striking similarities with the site-specific DNA-binding domain (DBD) of Drosophila P element transposase, including a similar size, N-terminal location, and conservation of the residues that define the THAP motif, such as the C2CH signature (Cys-Xaa2–4-Cys-Xaa35–50-Cys-Xaa2-His). Our results suggest that the THAP domain is a novel example of a DBD that is shared between cellular proteins and transposases from mobile genomic parasites. [Copyright &y& Elsevier]