The Heterochromatic Barrier to DNA Double Strand Break Repair: How to Get the Entry Visa

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.

Ataxia Telangiectasia Mutated (ATM) Is Dispensable for Endonuclease I-SceI-induced Homologous Recombination in Mouse Embryonic Stem Cells

“…The I-SceI-based reporter system is not designed for detecting such a role. In addition, DSBs in heterochromatin activate ATM signaling in part to enhance heterochromatin relaxation, thus facilitating DSB repair by HR or NHEJ in this highly compact, transcriptionally inert chromatin environment (24). However, the HR we measured in this study occurs at the euchromatic ROSA26 locus (49).…”

“…4) In proliferating cells, although the majority (ϳ85%) of IR-induced DSBs are likely repaired by NHEJ with fast kinetics in an ATM-independent manner, repair of the remaining ϳ15% of IR-induced DSBs is dependent upon ATM and has slower repair kinetics that may reflect either NHEJ-mediated repair in heterochromatin or a possible HR-directed postreplication repair process (23)(24)(25)(26). Unlike proliferating cells, Purkinje neurons require ATM for repairing the majority of IR-induced DSBs likely by NHEJ (27).…”

Nuclear position dictates DNA repair pathway choice

“…To gain insight into the cause of the DDR delay and HR repression promoted by the nuclear lamina environment, we considered the possibility that the repressive chromatin structure associated with the nuclear lamina (Padeken and Heun 2014) is involved in this phenomenon (Goodarzi and Jeggo 2012;Lemaître and Soutoglou 2014).…”

SMC5/6 is required for the formation of segregation-competent bivalent chromosomes during meiosis I in mouse oocytes

“…The pericentromeric heterochromatin region consists of densely packed repetitive sequences and is at high risk of aberrant recombination events when double-strand breaks within these regions are repaired via homologous recombination (HR) (Goodarzi and Jeggo, 2012). SMC5/6 prevents HR within repetitive sequences such as rDNA in yeast, and heterochromatin in Drosophila mitotic cells (Torres-Rosell et al, 2007;Chiolo et al, 2011).…”