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PARP2 促进复制压力应答下的 BIR 介导的端粒脆弱性。

PARP2 promotes Break Induced Replication-mediated telomere fragility in response to replication stress.

机构信息

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, 233S. 10th street, Philadelphia, PA, 19107, USA.

出版信息

Nat Commun. 2024 Apr 2;15(1):2857. doi: 10.1038/s41467-024-47222-7.

DOI:10.1038/s41467-024-47222-7
PMID:38565848
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10987537/
Abstract

PARP2 is a DNA-dependent ADP-ribosyl transferase (ARTs) enzyme with Poly(ADP-ribosyl)ation activity that is triggered by DNA breaks. It plays a role in the Base Excision Repair pathway, where it has overlapping functions with PARP1. However, additional roles for PARP2 have emerged in the response of cells to replication stress. In this study, we demonstrate that PARP2 promotes replication stress-induced telomere fragility and prevents telomere loss following chronic induction of oxidative DNA lesions and BLM helicase depletion. Telomere fragility results from the activity of the break-induced replication pathway (BIR). During this process, PARP2 promotes DNA end resection, strand invasion and BIR-dependent mitotic DNA synthesis by orchestrating POLD3 recruitment and activity. Our study has identified a role for PARP2 in the response to replication stress. This finding may lead to the development of therapeutic approaches that target DNA-dependent ART enzymes, particularly in cancer cells with high levels of replication stress.

摘要

PARP2 是一种 DNA 依赖性 ADP-ribosyl 转移酶 (ARTs) 酶，具有 Poly(ADP-ribosyl) 化活性，由 DNA 断裂触发。它在碱基切除修复途径中发挥作用，与 PARP1 具有重叠功能。然而，PARP2 在细胞对复制应激的反应中出现了额外的作用。在这项研究中，我们证明 PARP2 促进复制应激诱导的端粒脆弱性，并防止慢性诱导氧化 DNA 损伤和 BLM 解旋酶耗竭后端粒丢失。端粒脆弱性源自断裂诱导复制途径 (BIR) 的活性。在此过程中，PARP2 通过协调 POLD3 的募集和活性，促进 DNA 末端切除、链入侵和 BIR 依赖性有丝分裂 DNA 合成。我们的研究确定了 PARP2 在复制应激反应中的作用。这一发现可能导致针对 DNA 依赖性 ART 酶的治疗方法的发展，特别是在具有高水平复制应激的癌细胞中。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/95ace8bcd187/41467_2024_47222_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/2496d9125eb9/41467_2024_47222_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/701621c4ec92/41467_2024_47222_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/cf7d32051254/41467_2024_47222_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/fccb568f962a/41467_2024_47222_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/d111590726b4/41467_2024_47222_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/536043fdfa71/41467_2024_47222_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/8b1b9df65b07/41467_2024_47222_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/95ace8bcd187/41467_2024_47222_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/2496d9125eb9/41467_2024_47222_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/701621c4ec92/41467_2024_47222_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/cf7d32051254/41467_2024_47222_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/fccb568f962a/41467_2024_47222_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/d111590726b4/41467_2024_47222_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/536043fdfa71/41467_2024_47222_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/8b1b9df65b07/41467_2024_47222_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/68ed/10987537/95ace8bcd187/41467_2024_47222_Fig8_HTML.jpg

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