title: A macrohistone variant links dynamic chromatin compaction to BRCA1-dependent genome maintenance.
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.
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, NCI/NIH, Bethesda, MD 20892, USA.
authors.forename: Simran
authors.initials: S
authors.lastname: Khurana
authors.affiliation: Experimental Immunology Branch, NCI/NIH, Bethesda, MD 20892, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kruhlak
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, NCI/NIH, Bethesda, MD 20892, USA.
authors.forename: Jeongkyu
authors.initials: J
authors.lastname: Kim
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, NCI/NIH, Bethesda, MD 20892, USA.
authors.forename: Andy D
authors.initials: AD
authors.lastname: Tran
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, NCI/NIH, Bethesda, MD 20892, USA.
authors.forename: Jinping
authors.initials: J
authors.lastname: Liu
authors.affiliation: Mouse Cancer Genetics Program, NCI/NIH, Frederick, MD 21702, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Nyswaner
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA.
authors.forename: Parthav
authors.initials: P
authors.lastname: Jailwala
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, NCI/NIH, Bethesda, MD 20892, USA.
authors.forename: Myong-Hee
authors.initials: MH
authors.lastname: Sung
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 5290002, Israel.
authors.forename: Ofir
authors.initials: O
authors.lastname: Hakim
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, NCI/NIH, Bethesda, MD 20892, USA. Electronic address: philipp.oberdoerffer@nih.gov.
authors.forename: Philipp
authors.initials: P
authors.lastname: Oberdoerffer
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D019313:BRCA1 Protein / Q000502:physiology*; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000378:metabolism; D042822:Genomic Instability; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000502:physiology*; D006801:Humans; D008745:Methylation; D009687:Nuclear Proteins / Q000378:metabolism; D020033:Protein Isoforms / Q000502:physiology; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D059767:Recombinational DNA Repair; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; D020033:Protein Isoforms; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; C093563:PRDM2 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins