A macrohistone variant links dynamic chromatin compaction to BRCA1-dependent genome maintenance

Simran Khurana, Michael J. Kruhlak, Jeongkyu Kim, Andy D. Tran, Jinping Liu, Katherine Nyswaner, Lei Shi, Parthav Jailwala, Myong Hee Sung, Ofir Hakim, Philipp Oberdoerffer

Research output: Contribution to journalArticlepeer-review

161 Scopus citations

Abstract

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, macroH2A1 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.

Original languageEnglish
Pages (from-to)1049-1062
Number of pages14
JournalCell Reports
Volume8
Issue number4
DOIs
StatePublished - 21 Aug 2014

Bibliographical note

Funding Information:
We thank Y. Dalal, T. Misteli, A. Nussenzweig, and S. Oberdoerffer for critical reading of the manuscript; S. Silver, T Nieland, and the Broad RNAi platform for assistance with RNAi screening; A. Mazumder for help with Cellomics high-content imaging; B. Tran and J. Shetty for Illumina sequencing; S. Burkett for FISH analysis; and C. Lukas, Y. Galanty, S. Jackson, D. Livingston, and A. Sartori for reagents. This work was supported by federal funds from the National Cancer Institute, NIH, and the NIH intramural research program.

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