Kub5‐Hera RPRD1B Regulates CDK1 Expression Through the DREAM Complex

Triple Negative Breast Cancer (TNBC) is a subtype with more aggressive, less differentiated capacity and enhanced metastatic ability. Although TNBC tumors are more responsive to neoadjuvant chemotherapy compared to receptor‐positive tumors, development of resistance to cytotoxic chemotherapy and early relapse is more common. Due to the lack of effective therapies, understanding the underlying mechanisms of TNBC aggressiveness and poor prognosis is a major focus of research with particular interest in identifying new therapeutic targets.Kub5‐HeraRPRD1B (K‐H) is a novel factor involved in preserving genomic stability and regulates BRCA1 function by mediating the expression of CDK1, a master regulator of cell cycle, DNA replication, and DNA repair. This regulation has been reported in MDA‐MB‐231 cells, a model of TNBC. However, the underlying mechanism regulated CDK1 expression by K‐H is unknown. Here, we found that the CDK1 promoter is essential for the recruitment of K‐H. We also examined the interaction between K‐H and the complex for the regulation of cell cycle‐dependent gene expression, DREAM complex (dimerization partner, RB‐like, E2F and multi‐vulval class B complex) by immunoprecipitation. The interaction between K‐H and the DREAM complex is further validated using a Proximity ligation assay (PLA). Furthermore, a mutation in K‐H (R106A) results in the loss of an interaction between K‐H and the DREAM complex as well as K‐H and RNAPII, leading to decreased CDK1 levels. These results suggest that CDK1 expression is upregulated by K‐H and its complex formation with the DREAM complex and RNAPII. Thus, we hypothesize that K‐H modulates CDK1 expression through the recruitment of the DREAM complex to the CDK1 promoter region in a sequence‐specific manner. Our studies reveal a novel strategy for developing therapies that target the interaction between K‐H and the DREAM complex, potentially inhibiting the growth of cancer cells.Support or Funding InformationThis work is supported by NIH grant 1 R01 CA201489‐04This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.