ZFP281-BRCA2 可防止 DNA 复制过程中 R 环的积累。
ZFP281-BRCA2 prevents R-loop accumulation during DNA replication.
机构信息
Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University, Nanjing, 210096, China.
Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
出版信息
Nat Commun. 2022 Jun 17;13(1):3493. doi: 10.1038/s41467-022-31211-9.
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.
R 环在哺乳动物基因组中普遍存在，并参与许多基本的细胞过程。BRCA2 的缺失会导致异常的 R 环积累，从而导致基因组不稳定。在这里，我们表明 ZFP281 与 BRCA2 合作，防止 R 环积累，从而促进胚胎干细胞中的 DNA 复制。ZFP281 的缺失会降低染色质上的 PCNA 水平，并损害 DNA 复制。在机制上，我们证明 ZFP281 可以与 BRCA2 相互作用，并且 BRCA2 在富含 G/C 的启动子上富集，并且需要 ZFP281 和 PRC2 才能将其正确募集到全基因组范围的双价染色质上。此外，ZFP281 或 BRCA2 的缺失会导致双价区域 R 环的积累，并损害视黄酸在干细胞分化过程中激活发育基因的能力。总之，我们的结果表明，ZFP281 将 BRCA2 募集到双价染色质区域，以确保通过防止持续的 R 环来正确推进 DNA 复制。
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