BRCA1 Is Phosphorylated at Serine 1497 In Vivo at a Cyclin-Dependent Kinase 2 Phosphorylation Site

The Salk Institute, La Jolla, California 92037, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 08/1999; 19(7):4843-54. DOI: 10.1128/MCB.19.7.4843
Source: PubMed


BRCA1 is a cell cycle-regulated nuclear protein that is phosphorylated mainly on serine and to a lesser extent on threonine residues. Changes in phosphorylation occur in response to cell cycle progression and DNA damage. Specifically, BRCA1 undergoes hyperphosphorylation during late G
and S phases of the cell cycle. Here we report that BRCA1 is phosphorylated in vivo at serine 1497 (S1497), which is part of a cyclin-dependent kinase (CDK) consensus site. S1497 can be phosphorylated in vitro by CDK2-cyclin A or E. BRCA1 coimmunoprecipitates with an endogenous serine-threonine protein kinase activity that phosphorylates S1497 in vitro. This cellular kinase activity is sensitive to transfection of a dominant negative form of CDK2 as well as the application of the CDK inhibitors p21 and butyrolactone I but not p16. Furthermore, BRCA1 coimmunoprecipitates with CDK2 and cyclin A. These results suggest that the endogenous kinase activity is composed of CDK2-cyclin complexes, at least in part, concordant with the G
/S-specific increase in BRCA1 phosphorylation.

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    • "Cyclin E1 has the highest affinity for CDK2, its main binding partner in actively cycling cells (72–74), and CDK1 (CDC2) (75). Both CDK2 and CDK1 directly phosphorylate BRCA1 (76, 77) (Figure 2A). Furthermore, a functional link between CDK1 and BRCA1 has been established in lung cancer. "
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    ABSTRACT: Resistance to platinum chemotherapy is one of the main factors driving ovarian cancer mortality, and overcoming platinum resistance is considered one of the greatest challenges in ovarian cancer research. Genetic and functional evidence points to the homologous recombination (HR) DNA repair system, and BRCA1 and BRCA2 in particular, as main determinants of response to platinum therapy. BRCA-mutant ovarian cancers are especially sensitive to platinum, associated with better survival, and amenable to poly ADP ribose polymerase inhibitor treatment. Here, we discuss a therapeutic concept that seeks to disrupt HR capacity via targeting of BRCA1 and BRCA2 functionality in order to reverse platinum resistance in BRCA-proficient high-grade serous ovarian cancers (HGSOC). We review the molecular signaling pathways that converge on BRCA1 and BRCA2, their activation status in ovarian cancer, and therapeutic options to modulate BRCA function. Several recent publications demonstrate efficient chemosensitization of BRCA-proficient cancers by combining targeted therapy with standard platinum-based agents. Due to its inherent genomic heterogeneity, molecularly defined subgroups of HGSOC may require different approaches. We seek to provide an overview of available agents and their potential use to reverse platinum resistance by inhibiting the HR system, either directly or indirectly, by targeting oncogenic activators of HR.
    Frontiers in Oncology 03/2014; 4:34. DOI:10.3389/fonc.2014.00034
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    • "The sixteen biologically characterized phosphorylation sites for BRCA1 (Table S1 in File S1) studied are involved in functions including intracellular localization [46], [47], transcription regulation [48], and cell cycle regulation [39], [49]. Phosphorylation of BRCA2, on the other hand, is pertinent in regulating of BRCA2-mediated DNA recombination repair [44], [45]. "
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    PLoS ONE 05/2013; 8(5):e62468. DOI:10.1371/journal.pone.0062468 · 3.23 Impact Factor
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    • "As a genetic factor, the breast cancer susceptibility gene (BRCA1) is known to be responsible for half of all inherited cases (Nathanson et al., 2001). The function of BRCA1 has been reported to be involved in tumor suppression (Deng and Brodie, 2000), DNA repair (Scully et al., 1997), cell cycle checkpoint control (Ruffner et al., 1999), and ubiquitination (Jensen et al., 1998). In addition, we have demonstrated that BRCA1 plays a crucial role in cellular † CORRESPONDING AUTHOR: Department of Oncology and Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, Tel, 1-202-687-5267; Fax, 1-202-687-2847; "
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