Journal Article

Cancer mutations in RAD51 and its paralogues

Huth, Isabella L., Valentine, Anna L., Rabbani, Aisha Z., Duff, Nika M., Bouley, Renee A., Petreaca, Ruben C., Donahue, Kateri N., Bush, Wesley A.

2026

Overview

The RAD51 recombinase is central to repair of DNA damage arising from stalled or collapsed replication forks and DNA double strand breaks. Its essential role is revealed by the fact that this function evolved in bacteria but was retained in eukaryotes. In humans some of the RAD51 functions have been relegated to several paralogues which evolved by gene duplication. In addition to mutations, most cancers are also characterized by increased chromosomal instability manifesting as translocations, deletions, insertions, and other more complex forms of chromosomal re-arrangements. Given the central role of RAD51 in protecting against chromosomal instability it stands to reason that RAD51 mutations that alter its function should register in cancer cells. However, pan-cancer analyses of analyzed cancer genomes show a marked absence of RAD51 loss of function mutations leading to a so-called “RAD51 paradox”: increased chromosomal instability despite normal RAD51 function. One hypothesis is that mutations in the RAD51 paralogues may contribute to the genomic instability, meaning that a lack of mutations in RAD51 may be compensated by an increase of mutations in the paralogues. We queried analyzed cancer genomes from COSMIC and mapped all mutations in RAD51 and its paralogues. This revealed an increase in RAD51B, RAD51C and RAD51D paralogue mutations in human cancers. We used established algorithms to determine the probability that any mutation may affect enzyme function. Although, we did not find many “driver” mutations, numerous paralogue mutations were pathogenic or likely to destabilize enzyme function. In silico 3D structure analysis was then used to analyze the potential effect of some of these mutations on protein structure. Gene expression analysis did not reveal any changes in paralogue expression levels. Further, an evolutionary analysis did not uncover any selective pressure for mutations in RAD51 and its paralogues. A comparison of mutations reported on COSMIC with those reported on ClinVar revealed that many mutations primarily in RAD51C and RAD51D are also hereditary. Thus, it appears that an apparent low level of RAD51 mutations in cancer cells is compensated by an increase in paralogues mutations.

• Publisher: Public Library of Science,PLOS
• Subject: Algorithms / Analysis / Biology and Life Sciences / Cancer / Chromosomal Instability / Chromosome translocations / Comparative analysis / Deoxyribonucleic acid / DNA / DNA biosynthesis / DNA damage / DNA repair / Enzymes / Eukaryotes / Gene duplication / Gene expression / Gene mutations / Genes / Genetic aspects / Genomes / Genomic instability / Genomics / Humans / Medicine and Health Sciences / Mutation / Neoplasms - genetics / Physical Sciences / Physiological aspects / Protein structure / Proteins / Rad51 Recombinase - chemistry / Rad51 Recombinase - genetics / Rad51 Recombinase - metabolism / Recombinase / Recombinases / Replication forks / Stability / Structural analysis