Pan-cancer analysis of co-occurring mutations in RAD52 and the BRCA1-BRCA2-PALB2 axis in human cancers

被引:4
|
作者
Hamid, Abdulaziz B. [1 ]
Frank, Lauren E. [2 ]
Bouley, Renee A. [3 ]
Petreaca, Ruben C. [4 ,5 ]
机构
[1] Med Coll Wisconsin, Milwaukee, WI 53226 USA
[2] Ohio State Univ, Zool Undergrad Program, Marion, OH USA
[3] Ohio State Univ, Dept Chem & Biochem, Marion, OH 43302 USA
[4] Ohio State Univ Marion, Dept Mol Genet, Marion, OH 43302 USA
[5] Ohio State Univ, Canc Biol Program, James Comprehens Canc Ctr, Columbus, OH 43210 USA
来源
PLOS ONE | 2022年 / 17卷 / 09期
基金
美国国家卫生研究院;
关键词
CONSERVATIVE HOMOLOGOUS RECOMBINATION; CYCLE-DEPENDENT REPAIR; CELL-CYCLE; SYNTHETICALLY LETHAL; DNA-REPAIR; VARIANTS; BRCA1; INACTIVATION; INSTABILITY; MECHANISM;
D O I
10.1371/journal.pone.0273736
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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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页数:17
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