Repair of DNA Double-Strand Breaks in Heterochromatin

Abstract

DNA double-strand breaks (DSBs) are among the most damaging lesions in DNA, since, if not identified and repaired, they can lead to insertions, deletions or chromosomal rearrangements. DSBs can be in the form of simple or complex breaks, and may be repaired by one of a number of processes, the nature of which depends on the complexity of the break or the position of the break within the chromatin. In eukaryotic cells, nuclear DNA is maintained as either euchromatin (EC) which is loosely packed, or in a denser form, much of which is heterochromatin (HC). Due to the less accessible nature of the DNA in HC as compared to that in EC, repair of damage in HC is not as straightforward as repair in EC. Here we review the literature on how cells deal with DSBs in HC.

Heterochromatin and DNA damage repair: Use different histone variants and relax

“…However, the compact nature of heterochromatin poses an obstacle to DDR and repair; it has been noted that heterochromatin accumulates more mutations than less condensed euchromatin. 3,29 It also appears that DDR in heterochromatin is facilitated by distinct mechanisms. 1,3,16 In mammals, a specific DDR pathway involving HP1 and KAP1 proteins that are phosphorylated by ATM facilitates DSB repair in heterochromatin.…”

“…3,29 It also appears that DDR in heterochromatin is facilitated by distinct mechanisms. 1,3,16 In mammals, a specific DDR pathway involving HP1 and KAP1 proteins that are phosphorylated by ATM facilitates DSB repair in heterochromatin. As a consequence, HP1 is released from chromatin leading to heterochromatin relaxation.…”

“…Together, these features of histones have a strong impact on nucleosome stability and the binding of chromatin interacting and regulatory factors, and influence chromatin organization in response to DNA damage. [1][2][3][4] A network of conserved multiprotein complexes assembles at DNA double-strand breaks (DSBs) and recruits and activates members of the phosphatidylinositol 3-kinase-related kinase (PIKK) family. In mammals and plants, the ataxia telangiectasia mutated (ATM) kinase is the primary kinase activated in response to DSBs.…”

“…These regions can be visualized as discrete gH2A.X foci throughout the nucleoplasm in metazoan and plant nuclei. [1][2][3][4][5][6] In plants, phosphorylation of H2A.X and formation of gH2A.X foci depend on ATM, primarily. The activity of another PIKK kinase, ATM and Rad3-related (ATR) that responds to singlestranded DNA and stalled replication forks, accounts for 10% of gH2A.X foci.…”

Site-specific targeting of a light activated dCas9-KIllerRed fusion protein generates transient, localized regions of oxidative DNA damage

“…acetylation (12,13). In addition, compact chromatin structures such as heterochromatin have reduced DSB repair efficiency and require dedicated remodeling events, such as phosphorylation of KAP1 (14), to promote access to and repair of damage in these regions (15). These processes function together to modulate chromatin accessibility at damage sites (16,17), so that chromatin conformation does not impede the access of the DNA repair machinery to the damaged chromatin (18)(19)(20)(21)(22).…”