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Cancer Research Frontiers. 2014 Feb; 1(1): 49-59. doi: 10.17980/2015.49

NFBD1/MDC1: DNA damage response, cell cycle regulation and carcinogenesis

Toshinori Ozaki1*, Youquan Bu1, Hiroki Nagase2*

1Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan;

2Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan

*Corresponding author: Toshinori Ozaki, Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan, Tel.: +81-43-264-5431; Fax: +81-43-265-4459; E-mail: tozaki@chiba-cc.jp; Hiroki Nagase, Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan, Tel.: +81-43-264-5431; Fax: +81-43-265-4459; E-mail: hnagase@chiba-cc.jp

Citation: Ozaki T, et al. NFBD1/MDC1: DNA damage response, cell cycle regulation and carcinogenesis. Cancer Research Frontiers. 2015 Feb; 1(1): 49-59. doi: 10.17980/2015.49

Copyright: @ 2015 Ozaki T, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Competing Interests: The authors declare that they have no competing interests.

The abbreviations used are: ADR, adriamycin; APC/C, anaphase promoting complex/cyclosome; ATM, ataxia-telangiectasia-mutated; ATR, ataxia telangiectasia mutated and Rad3-related; BRCA1, breast cancer susceptibility gene 1; BRCT, BRCA1 C-terminus; CBP, CREB-binding protein; CDDP, cisplatin; CDK, cyclin-dependent kinase; DNAPK, DNA-dependent protein kinase; Emi1, early mitotic inhibitor 1; EMT, epitherial-mesenchymal transition; FHA, forkhead-associated; 53BP1, p53-binding protein 1; MDC1, mediator of DNA damage checkpoint protein 1; MRE11, meiotic recombination 11; MRN, MRE11/RAD50/NBS1; NBS1, nijmegen breakage syndrome 1; NFBD1, nuclear factor with BRCT domains protein 1; PIKK, phosphatidylinositol 3-kinase-related kinase; Plk-1, polo-like kinase 1; PP4, protein phosphatase 4; PST, proline/serine/threonine-rich repeat; RNF8, ring finger protein 8: Sp1, specificity protein 1; Wip1, wild-type p53-induced phosphatase 1.

Received Nov 17, 2014; Revised Jan 30, 2015; Accepted Feb 8, 2015; Published Feb 28, 2015.

 

Abstract

The cellular genome is constantly exposed to the endogenous as well as the exogenous DNA damages. Thus, the proper cellular response to DNA damage plays a critical role to maintain genomic integrity and acts as a molecular barrier against carcinogenesis. Without such DNA damage response, cells eventually pass on the damaged DNA to daughter cells, leading to the malignant transformation. When DNA damage is excessive, cells undergo apoptotic cell death. A growing body of evidence strongly suggests that one of the earliest events which takes place at chromatin surrounding the DNA damage is the phosphorylation of the histone H2A variant H2AX at Ser-139 (γ-H2AX) to generate nuclear foci. γ-H2AX acts as a docking site for DNA damage response/DNA repair proteins. NFBD1/MDC1 interacts with γ-H2AX through its BRCT domain and promotes the efficient recruitment of these proteins at the sites of DNA damage. Since NFBD1-deficient mice displayed the remarkable DNA repair defect and genomic instability, it is likely that NFBD1 plays an important role in the regulation of DNA damage response. In addition to DNA damage response, NFBD1 is closely involved in the regulation of mitotic progression. Recent studies demonstrated that NFBD1 interacts with the mitotic regulator APC/C and enhances its E3 ubiquitin protein ligase activity. In the present review article, we describe the functional significance of NFBD1 in the regulation of DNA damage response, cell cycle progression and carcinogenesis.

Keywords: ATM, cell cycle, DNA damage, γ-H2AX, NFBD1/MDC1

 

 

 

 

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