Abstract
Over recent decades, a deep understanding of pathways that repair DNA double strand breaks (DSB) has been gained from biochemical, structural, biophysical and cellular studies. DNA non-homologous end-joining (NHEJ) and homologous recombination (HR) represent the two major DSB repair pathways, and both processes are now well understood. Recent work has demonstrated that the chromatin environment at a DSB significantly impacts upon DSB repair and that, moreover, dramatic modifications arise in the chromatin surrounding a DSB. Chromatin is broadly divided into open, transcriptionally active, euchromatin (EC) and highly compacted, transcriptionally inert, heterochromatin (HC), although these represent extremes of a spectrum. The HC superstructure restricts both DSB repair and damage response signaling. Moreover, DSBs within HC (HC-DSBs) are rapidly relocalized to the EC-HC interface. The damage response protein kinase, ataxia telangiectasia mutated (ATM), is required for HC-DSB repair but is dispensable for the relocalization of HC-DSBs. It has been proposed that ATM signaling enhances HC relaxation in the DSB vicinity and that this is a prerequisite for HC-DSB repair. Hence, ATM is essential for repair of HC-DSBs. Here, we discuss how HC impacts upon the response to DSBs and how ATM overcomes the barrier that HC poses to repair.
Highlights
A broad range of studies including biochemical, structural and biophysical approaches have provided substantial detail and insight into the two most significant pathways of DNA double strand break (DSB) repair, namely DNA non-homologous end-joining (NHEJ) and homologous recombination (HR)
Whilst our understanding of the mechanisms underlying many of these chromatin changes and the rationale for them remains in their infancy, the changes that take place at HC-DSBs have a marked impact on DSB repair and damage response signaling
(1) DSBs elicit ataxia telangiectasia mutated (ATM) activation and irradiation induced foci formation (IRIF) formation, repair processes within heterochromatin are inhibited by the compacted nucleosome configuration produced by KRAB-associated protein 1 (KAP-1) dependent CHD3 activity; (2) Active ATM phosphorylates KAP-1 at S824, which interferes with the SUMOylation-dependent retention of CHD3 in chromatin; (3) In the absence of CHD3, the chromatin surrounding the DSB site relaxes, allowing (3A)
Summary
A broad range of studies including biochemical, structural and biophysical approaches have provided substantial detail and insight into the two most significant pathways of DNA double strand break (DSB) repair, namely DNA non-homologous end-joining (NHEJ) and homologous recombination (HR). There is increasing evidence that a significant role of the DNA damage response kinase, ataxia telangiectasia mutated (ATM), is to modify the chromatin environment in the DSB vicinity Whilst these modifications can include changes in phosphorylation, ubiquitylation, SUMOylation and methylation, many of which enhance chromatin relaxation, there is, paradoxically, evidence that proteins promoting chromatin compaction, such as KAP-1, HP1 and HDACs, can become relocalized and/or recruited to DSBs [1,2,3,4]. Somewhat distinct to the situation in mammalian cells, there is striking overlap These findings demonstrate two important aspects of DDR signaling; firstly, they provide strong evidence that modifications to the chromatin that arise during the DDR are inhibited by the HC superstructure and secondly, they demonstrate that DSBs formed within HC regions migrate to the periphery of such regions where DDR modifications ensue. Formally it is possible that HC is not intrinsically restrictive to histone modifications but rather that the regions of HC with DSBs become relocalized to HC-EC interface regions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
