BMAL2 in ovarian clear cell carcinoma
Ovarian clear cell carcinoma (OCCC) is highly chemo-resistant and has worse clinical outcome at advanced stages than other ovarian cancer subtypes.  The most frequent (~50%) alterations in OCCC are AT-rich interactive domain 1A gene (ARID1A) mutations which lead to ARID1A deficiency.  However, OCCC that retains ARID1A function differs substantially from ARID1A mutated OCCC.  Particularly, targeted therapies that sensitize ARID1A-deficient OCCC to DNA damage are largely ineffective against OCCC with wild-type (wt) ARID1A.  Thus, it is important to identify druggable targets and develop targeted therapies specifically for ARID1A-wt OCCC.  We identified BMAL2 as a critical OCCC oncogene that promotes tumorigenesis by preventing DNA damage from endogenous origins.  BMAL2 depletion altered expression of genes in DNA damage repair pathways, including RAD51, a core enzyme of the homologous recombination (HR) pathway.  This led to double-stranded break accumulation, decreased cell viability and reduced tumor growth.  This dependence on BMAL2 to maintain DNA integrity and cell viability can be a new route to suppress ARID1A-wt OCCC.