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

Monday, September 22, 2014 — Poster Session II
4:00 p.m. – 6:00 p.m.	FAES Academic Center	NCI	MOLBIO-7

* FARE Award Winner

Authors

• S Khurana
• M. J. Kruhlak
• J Kim
• A.D. Tran
• J Liu
• K Nyswaner
• L Shi
• P Jailwala
• M Sung
• O Hakim
• P Oberdoerffer

Abstract

Appropriate DNA double-strand break (DSB) repair factor choice is essential to ensure accurate repair outcome and genomic integrity. The factors that regulate this process remain poorly understood. Here, we identify two repressive chromatin components, the macro-histone variant macroH2A1 and the H3K9 methyltransferase and tumor suppressor PRDM2, which together modulate 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 ATM-dependent accumulation of both proteins at DSBs to promote DSB-flanking H3K9-dimethylation. Remarkably, loss of macroH2A1 or PRDM2 as well as experimentally induced chromatin decondensation impairs BRCA1, but not 53BP1 retention at DSBs. As a result, depletion of macroH2A1 and/or PRDM2 causes epistatic defects in DSB end resection, homology-directed repair and the resistance to 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.

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