Abstract
BRCA1 is an important player in the DNA damage response signaling, and its deficiency results in genomic instability. A complete loss or significantly reduced BRCA1 protein expression is often found in sporadic breast cancer cases despite the absence of genetic or epigenetic aberrations, suggesting the existence of other regulatory mechanisms controlling BRCA1 protein expression. Herein, we demonstrate that Fyn-related kinase (Frk)/Rak plays an important role in maintaining genomic stability, possibly in part through positively regulating BRCA1 protein stability and function via tyrosine phosphorylation on BRCA1 Tyr1552. In addition, Rak deficiency confers cellular sensitivity to DNA damaging agents and poly(ADP-ribose) polymerase (PARP) inhibitors. Overall, our findings highlight a critical role of Rak in the maintenance of genomic stability, at least in part, through protecting BRCA1 and provide novel treatment strategies for patients with breast tumors lacking Rak.
Highlights
The tumor suppressor BRCA1 plays essential roles in various cellular processes, including cell cycle checkpoint control [1], DNA repair [2], apoptosis [3, 4], transcriptional regulation [5, 6] and chromatin remodeling [7]
Rak deficiency causes spontaneous DNA damage due to defective double-strand breaks (DSBs) repair Based upon our previous findings that Rak positively regulates the stability and function of phosphatase and tensin homolog (PTEN) [25], together with mounting evidence demonstrating a role of PTEN in the maintenance of genomic stability [38, 39], we hypothesized that Rak, too, may be involved in maintaining genomic stability
Accumulating evidence suggests that BRCA1 protein levels can be regulated by the ubiquitin-proteasome pathway [19, 56, 60]
Summary
The tumor suppressor BRCA1 plays essential roles in various cellular processes, including cell cycle checkpoint control [1], DNA repair [2], apoptosis [3, 4], transcriptional regulation [5, 6] and chromatin remodeling [7]. Studies have shown that about 30~40% of patients with sporadic breast cancer have complete loss or significantly reduced expression of BRCA1 protein despite carrying an intact BRCA1 gene [10,11,12,13,14,15]. Loss of BRCA1 expression and/or function has been shown to be significantly associated with highly aggressive metastatic breast tumor phenotype [16, 17] and a poor prognosis [18]. Disruption of BRCA1 protein stability represents a very attractive mechanism to be studied, the molecular mechanisms responsible for the stability of BRCA1 protein remain to be elucidated
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