UPMC Hillman Cancer Center, University of Pittsburgh Cancer Institute, Department of Pharmacology and Chemical Biology, Pittsburgh, PA 15213, USA.
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Nucleic Acids Res. 2023 Mar 21;51(5):2215-2237. doi: 10.1093/nar/gkad066.
PARP1 is a DNA-dependent ADP-Ribose transferase with ADP-ribosylation activity that is triggered by DNA breaks and non-B DNA structures to mediate their resolution. PARP1 was also recently identified as a component of the R-loop-associated protein-protein interaction network, suggesting a potential role for PARP1 in resolving this structure. R-loops are three-stranded nucleic acid structures that consist of a RNA-DNA hybrid and a displaced non-template DNA strand. R-loops are involved in crucial physiological processes but can also be a source of genome instability if persistently unresolved. In this study, we demonstrate that PARP1 binds R-loops in vitro and associates with R-loop formation sites in cells which activates its ADP-ribosylation activity. Conversely, PARP1 inhibition or genetic depletion causes an accumulation of unresolved R-loops which promotes genomic instability. Our study reveals that PARP1 is a novel sensor for R-loops and highlights that PARP1 is a suppressor of R-loop-associated genomic instability.
聚腺苷二磷酸核糖聚合酶 1（PARP1）是一种 DNA 依赖性 ADP-核糖基转移酶，具有 ADP-核糖基化活性，可被 DNA 断裂和非 B DNA 结构触发，以介导其解析。PARP1 最近也被鉴定为 R 环相关蛋白-蛋白相互作用网络的一个组成部分，表明 PARP1 在解析这种结构中可能具有潜在作用。R 环是由 RNA-DNA 杂交体和一个取代的非模板 DNA 链组成的三链核酸结构。R 环参与关键的生理过程，但如果持续未解决，也可能成为基因组不稳定性的来源。在这项研究中，我们证明 PARP1 在体外与 R 环结合，并与细胞中 R 环形成位点相关联，从而激活其 ADP-核糖基化活性。相反，PARP1 的抑制或基因缺失会导致未解决的 R 环积累，从而促进基因组不稳定性。我们的研究表明，PARP1 是 R 环的一种新型传感器，并强调 PARP1 是 R 环相关基因组不稳定性的抑制剂。
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