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PARP1-TRIM44-MRN 环决定了对 PARP 抑制剂的反应。

PARP1-TRIM44-MRN loop dictates the response to PARP inhibitors.

机构信息

Department of Biochemistry, Ajou University School of Medicine, Suwon 16499, Republic of Korea.

Department of Biochemistry, Chungnam National University, Daejeon 34134, Republic of Korea.

出版信息

Nucleic Acids Res. 2024 Oct 28;52(19):11720-11737. doi: 10.1093/nar/gkae756.

DOI:10.1093/nar/gkae756
PMID:39217466
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11514498/
Abstract

PARP inhibitors (PARPi) show selective efficacy in tumors with homologous recombination repair (HRR)-defects but the activation mechanism of HRR pathway in PARPi-treated cells remains enigmatic. To unveil it, we searched for the mediator bridging PARP1 to ATM pathways by screening 211 human ubiquitin-related proteins. We discovered TRIM44 as a crucial mediator that recruits the MRN complex to damaged chromatin, independent of PARP1 activity. TRIM44 binds PARP1 and regulates the ubiquitination-PARylation balance of PARP1, which facilitates timely recruitment of the MRN complex for DSB repair. Upon exposure to PARPi, TRIM44 shifts its binding from PARP1 to the MRN complex via its ZnF UBP domain. Knockdown of TRIM44 in cells significantly enhances the sensitivity to olaparib and overcomes the resistance to olaparib induced by 53BP1 deficiency. These observations emphasize the central role of TRIM44 in tethering PARP1 to the ATM-mediated repair pathway. Suppression of TRIM44 may enhance PARPi effectiveness and broaden their use even to HR-proficient tumors.

摘要

聚腺苷二磷酸核糖聚合酶（PARP）抑制剂在同源重组修复（HRR）缺陷的肿瘤中显示出选择性疗效，但 PARPi 处理细胞中 HRR 途径的激活机制仍然是个谜。为了揭示这一机制，我们通过筛选 211 个人类泛素相关蛋白，寻找将 PARP1 与 ATM 途径联系起来的介质。我们发现 TRIM44 是一种至关重要的介质，它可以将 MRN 复合物招募到受损的染色质上，而不依赖于 PARP1 活性。TRIM44 结合 PARP1 并调节 PARP1 的泛素化-PAR 化平衡，这有助于及时招募 MRN 复合物进行 DSB 修复。在暴露于 PARPi 后，TRIM44 通过其 ZnF UBP 结构域将其结合从 PARP1 转移到 MRN 复合物上。在细胞中敲低 TRIM44 会显著提高对奥拉帕利的敏感性，并克服由 53BP1 缺乏引起的对奥拉帕利的耐药性。这些观察结果强调了 TRIM44 在将 PARP1 连接到 ATM 介导的修复途径中的核心作用。抑制 TRIM44 可能会增强 PARPi 的有效性，并扩大其用途，甚至用于 HR 功能正常的肿瘤。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b5b/11514498/e42b1c11b2e0/gkae756fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b5b/11514498/2a9449236556/gkae756figgra1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b5b/11514498/eac406bf25c1/gkae756fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b5b/11514498/0939f092f95d/gkae756fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b5b/11514498/33ba794fbfd0/gkae756fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b5b/11514498/a078d44257fe/gkae756fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b5b/11514498/e42b1c11b2e0/gkae756fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b5b/11514498/2a9449236556/gkae756figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b5b/11514498/c34addd037c2/gkae756fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b5b/11514498/5a21eca52b0c/gkae756fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b5b/11514498/eac406bf25c1/gkae756fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b5b/11514498/0939f092f95d/gkae756fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b5b/11514498/33ba794fbfd0/gkae756fig5.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b5b/11514498/e42b1c11b2e0/gkae756fig7.jpg

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