PARP1
DNA损伤
非同源性末端接合
DNA修复
基因组不稳定性
生物
DNA
同源重组
聚ADP核糖聚合酶
核糖核酸
细胞生物学
合成致死
分子生物学
聚合酶
化学
遗传学
基因
作者
Haibo Yang,Emily M. Lachtara,Xiaojuan Ran,Jessica Hopkins,Parasvi S. Patel,Xueping Zhu,Yao Xiao,Laiyee Phoon,Boya Gao,Lee Zou,Michael S. Lawrence,Li Lan
标识
DOI:10.1038/s41467-023-41790-w
摘要
Abstract The roles of R-loops and RNA modifications in homologous recombination (HR) and other DNA double-stranded break (DSB) repair pathways remain poorly understood. Here, we find that DNA damage-induced RNA methyl-5-cytosine (m5C) modification in R-loops plays a crucial role to regulate PARP1-mediated poly ADP-ribosylation (PARylation) and the choice of DSB repair pathways at sites of R-loops. Through bisulfite sequencing, we discover that the methyltransferase TRDMT1 preferentially generates m5C after DNA damage in R-loops across the genome. In the absence of m5C, R-loops activate PARP1-mediated PARylation both in vitro and in cells. Concurrently, m5C promotes transcription-coupled HR (TC-HR) while suppressing PARP1-dependent alternative non-homologous end joining (Alt-NHEJ), favoring TC-HR over Alt-NHEJ in transcribed regions as the preferred repair pathway. Importantly, simultaneous disruption of both TC-HR and Alt-NHEJ with TRDMT1 and PARP or Polymerase θ inhibitors prevents alternative DSB repair and exhibits synergistic cytotoxic effects on cancer cells, suggesting an effective strategy to exploit genomic instability in cancer therapy.
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