期刊
CELLULAR SIGNALLING
卷 27, 期 2, 页码 326-339出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2014.11.016
关键词
DNA damage response signalling; Mps one binder 2; Cell cycle progression; p53 tumour suppressor protein; Cell cycle checkpoint activation; MRE11-RAD50-NBS1 protein complex
类别
资金
- AICR [11-0634]
- Ministry of National Education (Republic of Turkey)
- BBSRC [BB/I021248/1]
- Wellcome Trust [090090/Z/09/Z]
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- BBSRC [BB/I021248/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/I021248/1] Funding Source: researchfish
- Cancer Research UK [15394] Funding Source: researchfish
- Worldwide Cancer Research [11-0634] Funding Source: researchfish
Mps one binder proteins (MOBS) are conserved regulators of essential signalling pathways. Biochemically, human MOB2 (hMOB2) can inhibit NDR kinases by competing with hMOB1 for binding to NDRs. However, biological roles of hMOB2 have remained enigmatic. Here, we describe novel functions of hMOB2 in the DNA damage response (DDR) and cell cycle regulation. hMOB2 promotes DDR signalling, cell survival and cell cycle arrest after exogenously induced DNA damage. Under normal growth conditions in the absence of exogenously induced DNA damage hMOB2 plays a role in preventing the accumulation of endogenous DNA damage and a subsequent p53/p21-dependent G1/S cell cycle arrest. Unexpectedly, these molecular and cellular phenotypes are not observed upon NDR manipulations, indicating that hMOB2 performs these functions independent of NDR signalling. Thus, to gain mechanistic insight, we screened for novel binding partners of hMOB2, revealing that hMOB2 interacts with RAD50, facilitating the recruitment of the MRE11-RAD5O-NBS1 (MRN) DNA damage sensor complex and activated ATM to DNA damaged chromatin. Taken together, we conclude that hMOB2 supports the DDR and cell cycle progression. (C) 2014 Elsevier Inc. All rights reserved.
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