Oncotarget

Research Papers:

The role of Rak in the regulation of stability and function of BRCA1

Jung-Lye Kim _, Geun-Hyoung Ha, Loredana Campo, Mitchell F. Denning, Tarun B. Patel, Clodia Osipo, Shiaw-Yih Lin and Eun-Kyoung Breuer

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Oncotarget. 2017; 8:86799-86815. https://doi.org/10.18632/oncotarget.5717

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Abstract

Jung-Lye Kim1,2, Geun-Hyoung Ha1,2, Loredana Campo1,2, Mitchell F. Denning1,3, Tarun B. Patel4, Clodia Osipo1,3, Shiaw-Yih Lin5 and Eun-Kyoung Breuer1,2

1Oncology Institute, Cardinal Bernardin Cancer Center, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA

2Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA

3Department of Pathology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA

4Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA

5Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

Correspondence to:

Eun-Kyoung Breuer, e-mail: [email protected]

Shiaw-Yih Lin, e-mail: [email protected]

Keywords: BRCA1, Rak, tyrosine phosphorylation, DNA damage response, genomic stability

Received: August 06, 2015     Accepted: October 02, 2015     Published: October 14, 2015

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.


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