The Chromatin Landscape Channels DNA Double-Strand Breaks to Distinct Repair Pathways

Abstract

DNA double-strand breaks (DSBs), the most deleterious DNA lesions, are primarily repaired by two pathways, namely homologous recombination (HR) and non-homologous end joining (NHEJ), the choice of which is largely dependent on cell cycle phase and the local chromatin landscape. Recent studies have revealed that post-translational modifications on histones play pivotal roles in regulating DSB repair pathways including repair pathway choice. In this review, we present our current understanding of how these DSB repair pathways are employed in various chromatin landscapes to safeguard genomic integrity. We place an emphasis on the impact of different histone post-translational modifications, characteristic of euchromatin or heterochromatin regions, on DSB repair pathway choice. We discuss the potential roles of damage-induced chromatin modifications in the maintenance of genome and epigenome integrity. Finally, we discuss how RNA transcripts from the vicinity of DSBs at actively transcribed regions also regulate DSB repair pathway choice.

Keywords: DNA doube-strand breaks; RNA-DNA hybrids; euchromatin; heterochromatin; histone modifications; repair pathway choice; transcription.

FIGURE 1

Histone modifications involved in dictating the cell cycle phase specific DSB repair pathway choice. (A) Histone mark H4K20me1/2 is enriched in G1 phase of the cell cycle. 53BP1 binds to nucleosomes containing both H4K20me1/2 and H2AK15ub, mediated by RNF168 upon DSB induction, to promote DSB repair by NHEJ (B) Unmethylated H4K20me0 is enriched in S/G2 phases of the cell cycle. BRCA1-BARD1 heterodimer recognizes H4K20me0 and H2AK15ub to facilitate HR repair (right). BRCA1 mediated H2AK129ub recruits SMARCAD1 to promote DNA end resection and thus HR (left).

FIGURE 2

Summary of different chromatin environments that promote DSB repair by HR. (A) In euchromatin, transcriptionally active histone mark H3K36me3 and H4K16ac promote DSB repair by HR (B) At peri-centromeric heterochromatin, histone repressive mark H3K9me3 interacts with Tip60 to acetylate H4K16 to attenuate 53BP1 recruitment. MBTD1, a subunit of Tip60/NuA4 complex, competes with 53BP1 form H4K20me1/2 to promote HR repair. Upon DSB induction, UFL1 mediates ufmylation on H4K31, which recruit histone lysine methyltransferase SUV39H1 to increase H3K9me3 and thereby promote HR (C) At centromeres in G1 phase, H3K4me2 promotes non-coding RNA transcription and RNA-DNA hybrids formation, which recruits HR factors to DSBs. The centromere specific histone variant CENP-A promotes the recruitment of Rad51 for HR repair. The deubiquitylase USP11 stabilizes CENP-A chaperone HJURP and PALB2 to recruit RAD51 and BRCA1, respectively, for HR repair.

FIGURE 3

Summary of how non-coding RNAs induced by DSBs, promote DSB repair by NHEJ and HR. Small non-coding RNAs (diRNAs/DDRNAs) and long non-coding RNAs (dilncRNAs) generated from the vicinity of DSB sites promote 53BP1 recruitment and thus NHEJ repair (left). RNA-DNA hybrids, produced by RNAPII or RNAPIII around DSBs, promote DSB repair by HR.