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

Abstract

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.

F-box DNA Helicase 1 (FBH1) Contributes to the Destabilization of DNA Damage Repair Machinery in Human Cancers

“…Although this analysis may suggest that RAD52-FBH1 co-mutations may not be as tolerated in cancer cells, this interpretation has a major caveat. RAD52 is only 418 amino acids, while BRCA2 is 3418 amino acids, BRCA1 is 1863 amino acids, and PALB2 is 1186 amino acids [ 54 ]. Because we checked for any mutations between these genes regardless of their impact on the function of the protein, statistically speaking, it is more likely to find mutations between longer genes [ 55 ].…”

Interactions between the DNA Damage Response and the Telomere Complex in Carcinogenesis: A Hypothesis

“…Yes [18] Yes [18] Rad 51 Yes [19,20] Yes [21] Rad 52 Yes [22] Yes [22,23] Rad 54 Yes [24] Yes [25,26] c-Abl Yes [27,28] Yes [29] BRCA1-BRCA2 Yes [30,31] Yes [32] ** PARP-1 Yes [33][34][35] Yes [36] *** DNA-PK cs Yes [28,37] Yes [38] Artemis Yes [28,39] Yes [40] Cerunnos Yes [41] Yes [41] Ku70-Ku80 Yes [42,43] Yes [43,44] Ligase IV Yes [45,46] Yes [46] Fanconi Anemia Yes [47] Yes [46] ˆCtIP Yes [48] Yes [48,49] Rad17 Yes [50] Yes [51,52] 9-1-1 complex Yes [53] Yes [53] 14-3-3 complex Yes [28] Yes [54] CTC complex Yes ...…”

Susceptibility Genes Associated with Multiple Primary Cancers

“…Homologous recombination, critical for DNA doublestrand break repair, is conserved from bacteria to humans [92,93]. In mammalian cells, the BRCA1/2 protein is pivotal in HR, notably in forming RAD51 presynaptic filaments and safeguarding stalled replication forks [94]. In cases of BRCA1/2 gene mutations, RAD52 takes over the repair role through the RAD51-independent single-strand annealing (SSA) pathway, active especially in direct repeat regions [95][96][97] (Figure 2C).…”

“…In cases of BRCA1/2 gene mutations, RAD52 takes over the repair role through the RAD51-independent single-strand annealing (SSA) pathway, active especially in direct repeat regions [95][96][97] (Figure 2C). Blocking RAD52 activity in cancer cells lacking BRCA1/2 proves fatal [94], underscoring the critical importance of RAD52 in the DNA repair process. However, RAD52-mediated repair is less precise compared with the BRCA1/2-driven homologous recombination process [98].…”