The Role of UBL5 and CT55 in BRCA2-Deficient Cells

Abstract

BRCA2 is essential for genomic stability. BRCA2 deficiency results in severe proliferation defects and affects the viability of normal cells. Yet, loss of BRCA2 is known to lead to tumorigenesis. It is hypothesized that some cells acquire mutations in genes that allow the cells to survive in the absence of BRCA2. One such gene or genetic interactor of BRCA2 is TP53, which is mutated in many BRCA2-deficient tumors. Here, using a CRISPR activation screening, we identify CT55 and UBL5 as genetic interactors of BRCA2. Both CT55 and UBL5 rescue BRCA2-deficient mouse embryonic stem cells (mESCs). Though CT55’s function and mechanism by which rescues BRCA2 lethality is yet to be discovered, CT55 shows nuclear localization in BRCA2 proficient and deficient cells. UBL5 has a role in the loading of cohesin by the cohesin cofactor Sororin. UBL5 has a significant effect on cell viability in with respect to BRCA2. Interestingly, loss of UBL5 is more lethal for BRCA2 proficient cells than BRCA2 deficient cells.

Also, UBL5 loss induced cell lethality is rescued by silencing Cohesion unloader, WAPL, suggesting the regulation between UBL5 and cohesion in affecting the cell viability. While we hypothesize, BRCA2 could be potential cohesion unloader, future experiments will explore these mechanisms to better understand the potential role of BRCA2 in the cohesin complex.