ZFP281-BRCA2 prevents R-loop accumulation during DNA replication

Yan Wang, Binbin Ma, Xiaoxu Liu, Ge Gao, Zhuanzhuan Che, Menghan Fan, Siyan Meng, Xiru Zhao, Rio Sugimura, Hua Cao, Zhongjun Zhou, Jing Xie, Chengqi Lin () and Zhuojuan Luo ()
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Yan Wang: Southeast University
Binbin Ma: Tongji University
Xiaoxu Liu: Southeast University
Ge Gao: The University of Hong Kong
Zhuanzhuan Che: Southeast University
Menghan Fan: Southeast University
Siyan Meng: Southeast University
Xiru Zhao: Southeast University
Rio Sugimura: The University of Hong Kong
Hua Cao: Affiliated Hospital of Fujian Medical University
Zhongjun Zhou: The University of Hong Kong
Jing Xie: Tongji University
Chengqi Lin: Affiliated Hospital of Fujian Medical University
Zhuojuan Luo: Southeast University

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract R-loops are prevalent in mammalian genomes and involved in many fundamental cellular processes. Depletion of BRCA2 leads to aberrant R-loop accumulation, contributing to genome instability. Here, we show that ZFP281 cooperates with BRCA2 in preventing R-loop accumulation to facilitate DNA replication in embryonic stem cells. ZFP281 depletion reduces PCNA levels on chromatin and impairs DNA replication. Mechanistically, we demonstrate that ZFP281 can interact with BRCA2, and that BRCA2 is enriched at G/C-rich promoters and requires both ZFP281 and PRC2 for its proper recruitment to the bivalent chromatin at the genome-wide scale. Furthermore, depletion of ZFP281 or BRCA2 leads to accumulation of R-loops over the bivalent regions, and compromises activation of the developmental genes by retinoic acid during stem cell differentiation. In summary, our results reveal that ZFP281 recruits BRCA2 to the bivalent chromatin regions to ensure proper progression of DNA replication through preventing persistent R-loops.

Date: 2022
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DOI: 10.1038/s41467-022-31211-9

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