Defining biomarkers of “BRCAness” deficiency in the hereditary breast and ovarian cancer genes
Figure Legend: The current dogma proposes that chemotherapy directly or indirectly generates DSBs that are sensitizing to BRCA mutant cells
that have a DNA repair defect. We propose an alternative framework in which “BRCAness” relates to a lagging strand gap vulnerability due a
defect in gap suppression/repair.
Our recent work indicates that DNA replication single stranded DNA gaps (ssDNA) are the true cause of chemotherapy response in BRCA deficient cancer and therefore define BRCAness (Panzarino et al., Cancer Research and Cong et al., Molecular Cell 2021). Rather than an HRD score (homologous recombination deficiency) that relies on tumors being sensitive to chemotherapy based on DNA repair defects, our findings instead indicate responding tumors will be more accurately identified by a gap score. A key question is whether gaps cause protein changes that could signify gaps. To address this question, we performed a non-biased proteomic based approach. We found that as compared to BRCA-proficient cells, BRCA-deficient cells have distinct protein enrichments and reductions in replicating cells. Likewise, we found that BRCA-deficient cells that gain chemoresistance have a distinct set of protein changes that are also critical for gap suppression and chemoresistance. Thus, these enrichments provide an important set of proteins to target and enhance or restore chemosensitivity. Moreover, these proteins show unique nuclear patterns that are being considered for biomarkers of therapy response or BRCAness.