A Macrohistone Variant Links Dynamic Chromatin Compaction to BRCA1-Dependent Genome Maintenance

Abstract

SUMMARY Appropriate DNA double-strand break (DSB) repair factor choice is essential for ensuring accurate repair outcome and genomic integrity. The factors that regulate this process remain poorly understood. Here, we identify two repressive chromatin components, the macrohistone variant macroH2A1 and the H3K9 methyltransferase and tumor suppressor PRDM2, which together direct the choice between the antagonistic DSB repair mediators BRCA1 and 53BP1. The macroH2A1/PRDM2 module mediates an unexpected shift from accessible to condensed chromatin that requires the ataxia telangiectasia mutated (ATM)-dependent accumulation of both proteins at DSBs in order to promote DSB-flanking H3K9 dimethylation. Remarkably, loss of macroH2A1 or PRDM2, as well as experimentally induced chromatin decondensation, impairs the retention of BRCA1, but not 53BP1, at DSBs. As a result, mac-roH2A1 and/or PRDM2 depletion causes epistatic defects in DSB end resection, homology-directed repair, and the resistance to poly(ADP-ribose) polymerase (PARP) inhibition—all hallmarks of BRCA1-deficient tumors. Together, these findings identify dynamic, DSB-associated chromatin reorganization as a critical modulator of BRCA1-dependent genome maintenance.

Poly(ADP-ribosyl)ation-dependent Transient Chromatin Decondensation and Histone Displacement following Laser Microirradiation

“…The hypercondensation we and colleagues could observe in U2OS cells is an interesting effect that seems to be important for DNA damage response signaling (44), and proper recruitment of some repair proteins (45). Of all the cell types we tested, we only observed this in U2OS cells.…”

“…Because we have the reference behavior of histone H4, our results indicate that there is indeed a small amount of displacement of histone H2A-H2B dimers. Interestingly, macroH2A1.1 is assembled onto chromatin in a PARP-dependent manner (45,49). It may be that displacement of H2A-H2B dimers enables the incorporation of macroH2A1.1 into nucleosomes at sites of damage.…”

Histone modifications predispose genome regions to breakage and translocation

“…In addition, increased γ-H2AX foci formation occurs at a defined region of transcribed genes relative to a gene-poor region after irradiation (Falk et al 2008). Changes in histone modifications may also affect the progression of the DNA damage response (DDR) by interfering with the restoration of baseline chromatin structure after repair (Ayrapetov et al 2014;Burgess et al 2014;Khurana et al 2014), since, in ASH2L-expressing cells, recondensation at the site of DNA damage as well as upstream DDR signaling is dampened (Burgess et al 2014), and γ-H2AX foci formation after irradiation is associated with loss of H3K4me3 (Seiler et al 2011;Lafon-Hughes et al 2013;Maroschik et al 2014). These observations suggest that H3K4 hypermethylation may impair DDR progression by counteracting condensation and signaling required for efficient DDR, thus resulting in persistent DSBs and enhancing the likelihood of formation of translocations.…”

Repair of chromatinized DNA

“…Процесс начинается с диметилирования гис-тона H3 по позиции K9 и включения вариантной формы гистона H2A макроH2A1 [26].…”