Pan-cancer analysis of co-occurring mutations in RAD52 and the BRCA1-BRCA2-PALB2 axis in human cancers.
Pan-cancer analysis of co-occurring mutations in RAD52 and the BRCA1-BRCA2-PALB2 axis in human cancers.
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DOI：
10.1371/journal.pone.0273736
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
Petreaca, Ruben C.
中科院分区：
文献类型：
--
作者：
Hamid, Abdulaziz B.;Frank, Lauren E.;Bouley, Renee A.;Petreaca, Ruben C.
在人类细胞中，同源重组 (HR) 对于修复 DNA 双链断裂 (DSB) 以及挽救停滞或崩溃的复制叉至关重要。 HR 由 RAD51 促进，RAD51 通过 BRCA2-BRCA1-PALB2 或 RAD52 加载到 DNA 上。在人类培养细胞中，RAD52 和 BRCA1-BRCA2-PALB2 轴中基因的双重敲低是致命的。 BRCA2、BRCA1 或 PALB2 中的突变会显着损害无错误 HR，因为 RAD51 加载依赖于 RAD52，而 RAD52 不如 BRCA2-BRCA1-PALB2 熟练。 RAD52 还促进单链退火 (SSA)，从而产生染色体内缺失。一些影响 SSA 功能或减少 RAD52 与 DNA 关联的 RAD52 突变可以抑制乳腺癌中某些 BRCA2 相关表型。在本报告中，我们使用癌症体细胞突变目录 (COSMIC) 报告的数据进行了泛癌分析，以确定癌细胞中出现的 RAD52 和 BRCA1、BRCA2 或 PALB2 之间的双突变体。我们发现，某些癌症组织中可能会同时发生突变，但其他组织中则不然。然而，所有突变都以杂合状态发生。此外，使用计算和机器学习工具，我们仅识别出少数预计会显着影响蛋白质功能的致病突变或驱动突变。这支持了之前的研究结果，即 RAD52 与 BRCA2-BRCA1-PALB2 轴的任何成员共同失活是致命的。分子模型还表明，与 BRCA2-BRCA1-PALB2 轴突变同时发生的致病性 RAD52 突变预计会减弱其 SSA 功能或其与 DNA 的相互作用。这项研究将之前的乳腺癌研究结果扩展到其他癌症类型，并表明同时发生的突变可能通过与乳腺癌类似的机制破坏 HR 的稳定性。
In human cells homologous recombination (HR) is critical for repair of DNA double strand breaks (DSBs) and rescue of stalled or collapsed replication forks. HR is facilitated by RAD51 which is loaded onto DNA by either BRCA2-BRCA1-PALB2 or RAD52. In human culture cells, double-knockdowns of RAD52 and genes in the BRCA1-BRCA2-PALB2 axis are lethal. Mutations in BRCA2, BRCA1 or PALB2 significantly impairs error free HR as RAD51 loading relies on RAD52 which is not as proficient as BRCA2-BRCA1-PALB2. RAD52 also facilitates Single Strand Annealing (SSA) that produces intra-chromosomal deletions. Some RAD52 mutations that affect the SSA function or decrease RAD52 association with DNA can suppress certain BRCA2 associated phenotypes in breast cancers. In this report we did a pan-cancer analysis using data reported on the Catalogue of Somatic Mutations in Cancers (COSMIC) to identify double mutants between RAD52 and BRCA1, BRCA2 or PALB2 that occur in cancer cells. We find that co-occurring mutations are likely in certain cancer tissues but not others. However, all mutations occur in a heterozygous state. Further, using computational and machine learning tools we identified only a handful of pathogenic or driver mutations predicted to significantly affect the function of the proteins. This supports previous findings that co-inactivation of RAD52 with any members of the BRCA2-BRCA1-PALB2 axis is lethal. Molecular modeling also revealed that pathogenic RAD52 mutations co-occurring with mutations in BRCA2-BRCA1-PALB2 axis are either expected to attenuate its SSA function or its interaction with DNA. This study extends previous breast cancer findings to other cancer types and shows that co-occurring mutations likely destabilize HR by similar mechanisms as in breast cancers.
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DOI：
10.1093/bioinformatics/btt017
发表时间：
2013-03-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Douville C;Carter H;Kim R;Niknafs N;Diekhans M;Stenson PD;Cooper DN;Ryan M;Karchin R
通讯作者：
Karchin R
影响因子：
12.3
作者：
Brannon AR;Vakiani E;Sylvester BE;Scott SN;McDermott G;Shah RH;Kania K;Viale A;Oschwald DM;Vacic V;Emde AK;Cercek A;Yaeger R;Kemeny NE;Saltz LB;Shia J;D'Angelica MI;Weiser MR;Solit DB;Berger MF
通讯作者：
Berger MF
影响因子：
8.8
作者：
Brouwer, Ineke;Zhang, Hongshan;Modesti, Mauro
通讯作者：
Modesti, Mauro
影响因子：
4.4
作者：
Carter H;Douville C;Stenson PD;Cooper DN;Karchin R
通讯作者：
Karchin R
影响因子：
3.4
作者：
Frankenberg-Schwager, Marlis;Gebauer, Anja;Frankenberg, Dieter
通讯作者：
Frankenberg, Dieter