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C16orf72/HAPSTR1/TAPR1 与 BRCA1/Senataxin 一起发挥作用，调节与复制相关的 R 环，并赋予对 PARP 破坏的抗性。

C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption.

机构信息

Department of Biochemistry, University of Oxford, South Parks Road, Oxford, UK.

Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, UK.

出版信息

Nat Commun. 2023 Aug 17;14(1):5003. doi: 10.1038/s41467-023-40779-9.

DOI:10.1038/s41467-023-40779-9
PMID:37591890
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10435583/
Abstract

While the toxicity of PARP inhibitors to cells with defects in homologous recombination (HR) is well established, other synthetic lethal interactions with PARP1/PARP2 disruption are poorly defined. To inform on these mechanisms we conducted a genome-wide screen for genes that are synthetic lethal with PARP1/2 gene disruption and identified C16orf72/HAPSTR1/TAPR1 as a novel modulator of replication-associated R-loops. C16orf72 is critical to facilitate replication fork restart, suppress DNA damage and maintain genome stability in response to replication stress. Importantly, C16orf72 and PARP1/2 function in parallel pathways to suppress DNA:RNA hybrids that accumulate at stalled replication forks. Mechanistically, this is achieved through an interaction of C16orf72 with BRCA1 and the RNA/DNA helicase Senataxin to facilitate their recruitment to RNA:DNA hybrids and confer resistance to PARP inhibitors. Together, this identifies a C16orf72/Senataxin/BRCA1-dependent pathway to suppress replication-associated R-loop accumulation, maintain genome stability and confer resistance to PARP inhibitors.

摘要

虽然聚腺苷二磷酸核糖聚合酶（PARP）抑制剂对同源重组（HR）缺陷细胞的毒性已得到充分证实，但与 PARP1/PARP2 破坏的其他合成致死相互作用仍未得到明确界定。为了阐明这些机制，我们进行了全基因组筛选，以寻找与 PARP1/2 基因缺失具有合成致死性的基因，并发现 C16orf72/HAPSTR1/TAPR1 是一种新的复制相关 R-环的调节剂。C16orf72 对于促进复制叉重新启动、抑制 DNA 损伤以及维持复制应激下的基因组稳定性至关重要。重要的是，C16orf72 和 PARP1/2 以平行途径发挥作用，抑制在停滞复制叉处积累的 DNA:RNA 杂交体。从机制上讲，这是通过 C16orf72 与 BRCA1 和 RNA/DNA 解旋酶 Senataxin 的相互作用实现的，这有助于它们被招募到 RNA:DNA 杂交体上，并赋予对 PARP 抑制剂的抗性。总之，这确定了一种 C16orf72/Senataxin/BRCA1 依赖性途径，可抑制复制相关 R-环的积累，维持基因组稳定性并赋予对 PARP 抑制剂的抗性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae8b/10435583/3604ebe19d3b/41467_2023_40779_Fig7_HTML.jpg
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