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Tu ZG , Aird KM , Bitler BG , Nicodemus JP , Beeharry N , Xia B , Yen TJ , Zhang RG
Oncogenic Ras Regulates BRIP1 Expression to Induce Dissociation of BRCA1 from Chromatin, Inhibit DNA Repair, and Promote Senescence
Developmental Cell. 2011 Dec;21(6) :1077-1091
PMID: WOS:000298215200013    PMCID: PMC3241855   
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Abstract
Here, we report a cell-intrinsic mechanism by which oncogenic RAS promotes senescence while predisposing cells to senescence bypass by allowing for secondary hits. We show that oncogenic RAS inactivates the BRCA1 DNA repair complex by dissociating BRCA1 from chromatin. This event precedes senescence-associated cell cycle exit and coincides with the accumulation of DNA damage. Downregulation of BRIP1, a physiological partner of BRCA1 in the DNA repair pathway, triggers BRCA1 chromatin dissociation. Conversely, ectopic BRIP1 rescues BRCA1 chromatin dissociation and suppresses RAS-induced senescence and the DNA damage response. Significantly, cells undergoing senescence do not exhibit a BRCA1-dependent DNA repair response when exposed to DNA damage. Overall, our study provides a molecular basis by which oncogenic RAS promotes senescence. Because DNA damage has the potential to produce additional "hits" that promote senescence bypass, our findings may also suggest one way a small minority of cells might bypass senescence and contribute to cancer development.
Notes
Tu, Zhigang Aird, Katherine M. Bitler, Benjamin G. Nicodemus, Jasmine P. Beeharry, Neil Xia, Bing Yen, Tim J. Zhang, Rugang Nci[p50 ca083638, ca-009035-35]; dod[oc093420]; ocrf We thank Dr. Kathy Wilson and Igor Makhlin for reagents, other laboratory members for critical discussion, and Dr. Xinying Zhuang for technical assistance. We thank Drs. Hua-Ying Fan, Erica Golemis, and Maureen Murphy for critical reading of the manuscript. Z.T. performed most of the experiments, designed the experiments, and drafted the manuscript. K.M.A. contributed to Figure 4H and Figures S2C, S2D, S2F, S2G, and S4C. B.G.B. contributed to Figure 4D. J.P.N. contributed to initial observations that led to Figure 1A. N.B., B.X., and T.J.Y. provided critical materials and/or reagents. R.Z. conceived the study, designed experiments, and wrote the manuscript. R.Z. is an Ovarian Cancer Research Fund (OCRF) Liz Tilberis Scholar. This work was supported in part by an NCI FCCC-UPenn ovarian cancer SPORE (P50 CA083638) pilot project and SPORE career development award (to R.Z.), a DOD ovarian cancer academy award (OC093420 to R.Z.), and an OCRF program project (to R.Z.). B.G.B. is supported by an NCI postdoctoral training grant (CA-009035-35). We would like to acknowledge Anna Pecherskaya and Margret Einarson for help with quantitative image analysis and Emmanuelle Nicolas for help with microRNA qRT-PCR analysis. 55 Cell press Cambridge 864cs