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TRIM29 对于脊椎动物细胞中 53BP1 响应 DNA 双链断裂的有效募集是必需的。

TRIM29 is required for efficient recruitment of 53BP1 in response to DNA double-strand breaks in vertebrate cells.

机构信息

Section for Translational Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.

Research Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.

出版信息

FEBS Open Bio. 2020 Oct;10(10):2055-2071. doi: 10.1002/2211-5463.12954. Epub 2020 Aug 31.

DOI:10.1002/2211-5463.12954
PMID:33017104
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7530400/
Abstract

Tripartite motif-containing protein 29 (TRIM29) is involved in DNA double-strand break (DSB) repair. However, the specific roles of TRIM29 in DNA repair are not clearly understood. To investigate the involvement of TRIM29 in DNA DSB repair, we disrupted TRIM29 in DT40 cells by gene targeting with homologous recombination (HR). The roles of TRIM29 were investigated by clonogenic survival assays and immunofluorescence analyses. TRIM29 triallelic knockout (TRIM29) cells were sensitive to etoposide, but resistant to camptothecin. Foci formation assays to assess DNA repair activities showed that the dissociation of etoposide-induced phosphorylated H2A histone family member X (ɣ-H2AX) foci was retained in TRIM29 cells, and the formation of etoposide-induced tumor suppressor p53-binding protein 1 (53BP1) foci in TRIM29 cells was slower compared with wild-type (WT) cells. Interestingly, the kinetics of camptothecin-induced RAD51 foci formation of TRIM29 cells was higher than that of WT cells. These results indicate that TRIM29 is required for efficient recruitment of 53BP1 to facilitate the nonhomologous end-joining (NHEJ) pathway and thereby suppress the HR pathway in response to DNA DSBs. TRIM29 regulates the choice of DNA DSB repair pathway by facilitating 53BP1 accumulation to promote NHEJ and may have potential for development into a therapeutic target to sensitize refractory cancers or as biomarker of personalized therapies.

摘要

三结构域蛋白 29（TRIM29）参与 DNA 双链断裂（DSB）修复。然而，TRIM29 在 DNA 修复中的具体作用尚不清楚。为了研究 TRIM29 参与 DNA DSB 修复的情况，我们通过同源重组（HR）基因靶向敲除 DT40 细胞中的 TRIM29。通过集落形成实验和免疫荧光分析来研究 TRIM29 的作用。TRIM29 三等位基因敲除（TRIM29）细胞对依托泊苷敏感，但对喜树碱有抗性。用于评估 DNA 修复活性的焦点形成测定表明，依托泊苷诱导的磷酸化组蛋白家族成员 X（ɣ-H2AX）焦点的解离在 TRIM29 细胞中被保留，并且依托泊苷诱导的肿瘤抑制蛋白 p53 结合蛋白 1（53BP1）焦点在 TRIM29 细胞中的形成速度比野生型（WT）细胞慢。有趣的是，TRIM29 细胞中喜树碱诱导的 RAD51 焦点形成的动力学比 WT 细胞高。这些结果表明，TRIM29 对于 53BP1 的有效募集是必需的，以促进非同源末端连接（NHEJ）途径，并由此抑制对 DNA DSB 的同源重组（HR）途径。TRIM29 通过促进 53BP1 积累来调节 DNA DSB 修复途径的选择，以促进 NHEJ，并且可能具有作为治疗靶点以增敏难治性癌症或作为个性化治疗的生物标志物的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9354/7530400/d143a7bee458/FEB4-10-2055-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9354/7530400/d143a7bee458/FEB4-10-2055-g008.jpg
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