Functional Interaction Between BRCA1 and DNA Repair in Yeast May Uncover a Role of RAD50, RAD51, MRE11A, and MSH6 Somatic Variants in Cancer Development

Abstract

In this study, we determined if BRCA1 partners involved in DNA double-strand break (DSB) and mismatch repair (MMR) may contribute to breast and ovarian cancer development. Taking advantage the functional conservation of DNA repair pathways between yeast and human, we expressed several BRCA1 missense variants in DNA repair yeast mutants to identify functional interaction between BRCA1 and DNA repair in BRCA1-induced genome instability. The pathogenic p.C61G, pA1708E, p.M775R, and p.I1766S, and the neutral pS1512I BRCA1 variants increased intra-chromosomal recombination in the DNA-repair proficient strain RSY6. In the mre11, rad50, rad51, and msh6 deletion strains, the BRCA1 variants p.C61G, pA1708E, p.M775R, p.I1766S, and pS1215I did not increase intra-chromosomal recombination suggesting that a functional DNA repair pathway is necessary for BRCA1 variants to determine genome instability. The pathogenic p.C61G and p.I1766S and the neutral p.N132K, p.Y179C, and p.N550H variants induced a significant increase of reversion in the msh2Δ strain; the neutral p.Y179C and the pathogenic p.I1766S variant induced gene reversion also, in the msh6Δ strain. These results imply a functional interaction between MMR and BRCA1 in modulating genome instability. We also performed a somatic mutational screening of MSH6, RAD50, MRE11A, and RAD51 genes in tumor samples from 34 patients and identified eight pathogenic or predicted pathogenic rare missense variants: four in MSH6, one in RAD50, one in MRE11A, and two in RAD51. Although we found no correlation between BRCA1 status and these somatic DNA repair variants, this study suggests that somatic missense variants in DNA repair genes may contribute to breast and ovarian tumor development.

DNA Methylation and Hydroxymethylation in Cervical Cancer: Diagnosis, Prognosis and Treatment

“…However, BRCA1 functions differently as compared to DAPK1; BRCA1 is a tumor suppressor (Li et al, 2018a). It predominantly regulates DNA damage repair, transcription regulation, and apoptosis (Maresca et al, 2018;Sun et al, 2018). Therefore, it can serve as novel target during chemoradiation, like DAPK1.…”

“…DNA damage repair, transcriptional regulation and apoptosis Advantages: Decrease side effects Disadvantages: The overexpression of BRCA1 gene may improve tumorigenesis Li et al, 2018a;Maresca et al, 2018;Sood et al, 2018;Sun et al, 2018 Combine chemoradiation therapy with MGMT gene target MGMT Repair cytotoxic lesions by removing the methyl adducts from DNA Advantages: Decrease side effects Disadvantages: Not mentioned Jiapaer et al, 2018;Ren et al, 2018;Scicchitano et al, 2018;Sood et al, 2018;Yuan et al, 2018 Menthol by removing methyl adducts from DNA (Jiapaer et al, 2018;Scicchitano et al, 2018;Yuan et al, 2018), indicating MGMT can be a therapeutic target. Sood et al (2018) have also tested the potential of ESR1, MYOD1, and MLH1.…”

Inhibition of DNA Repair in Cancer Therapy: Toward a Multi-Target Approach

“…The most frequent mutated HR genes are BRCA1 and BRCA2, followed by RAD51, BLM, and RAD50 [46,47]. Germline mutations in BRCA1 and BRCA2 are related to the majority of hereditary breast and ovarian cancer (HBOC); however, beside these genes, several other low penetrance genes responsible of HBOC have been identified, such as PALB2 and RAD51 [48], and also mutations in genes coding for the components of the MRN complex [49,50].…”

“…Instead, germline mutations in MMR genes are associated with hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch Syndrome, an autosomal dominant disease. Moreover, mutations in all the MMR genes, MLH1 and MSH2, PMS2 and MSH6 have been found related to breast cancer susceptibility [50,[80][81][82][83][84].…”

Yeast-based assays for the functional characterization of cancer-associated variants of human DNA repair genes

“…Other assays to evaluate the impact of missense mutations in BRCA1 have been developed by our group. Since BRCA1 is involved in DNA repair, we developed two HR assays to evaluate the impact of variants on intra-and inter-chromosomal recombination (Figure 4E and 4F), and one assay to assess their effect on gene reversion (GR) at the ilv1-92 locus (Figure 4G) [65,76,77]. In our first explorative paper, we demonstrated the validity of the assay analyzing the effect of twelve BRCA1 variants (four pathogenic, seven neutral and one not classified) in a diploid yeast strain carrying the two different HR substrates to measure intra-chromosomal and inter-chromosomal recombination events [65].…”