QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 27 February 2007
doi: 10.1242/jcs.03391

This Article Figures Only Full Text Full Text (PDF) Supplementary Material All Versions of this Article: jcs.03391v1 120/6/1104    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Matsumoto, M. Articles by Matsunaga, T. Search for Related Content PubMed PubMed Citation Articles by Matsumoto, M. Articles by Matsunaga, T. Social Bookmarking                         What's this?

Perturbed gap-filling synthesis in nucleotide excision repair causes histone H2AX phosphorylation in human quiescent cells

¹ Laboratory of Human Molecular Genetics, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192, Japan
² Department of Biochemistry, Kanazawa Medical University, Ishikawa 920-0293, Japan
³ Radioisotope Research Center, Nara Medical University, Kashihara 634-8521, Japan
⁴ Central Laboratory and Radiation Biology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan

^* Author for correspondence (e-mail: matsukas{at}kenroku.kanazawa-u.ac.jp)

Accepted 4 January 2007

Human histone H2AX is rapidly phosphorylated on serine 139 in response to DNA double-strand breaks and plays a crucial role in tethering the factors involved in DNA repair and damage signaling. Replication stress caused by hydroxyurea or UV also initiates H2AX phosphorylation in S-phase cells, although UV-induced H2AX phosphorylation in non-cycling cells has recently been observed. Here we study the UV-induced H2AX phosphorylation in human primary fibroblasts under growth-arrested conditions. This reaction absolutely depends on nucleotide excision repair (NER) and is mechanistically distinct from the replication stress-induced phosphorylation. The treatment of cytosine--D-arabinofuranoside strikingly enhances the NER-dependent H2AX phosphorylation and induces the accumulation of replication protein A (RPA) and ATR-interacting protein (ATRIP) at locally UV-damaged subnuclear regions. Consistently, the phosphorylation appears to be mainly mediated by ataxia-telangiectasia mutated and Rad3-related (ATR), although Chk1 (Ser345) is not phosphorylated by the activated ATR. The cellular levels of DNA polymerases and and proliferating cell nuclear antigen are markedly reduced in quiescent cells. We propose a model that perturbed gap-filling synthesis following dual incision in NER generates single-strand DNA gaps and hence initiates H2AX phosphorylation by ATR with the aid of RPA and ATRIP.

Key words: Nucleotide excision repair, Histone H2AX, ATM and Rad3-related (ATR)

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				M. Kawanishi, T. Watanabe, S. Hagio, S. Ogo, C. Shimohara, R. Jouchi, S. Takayama, T. Hasei, T. Hirayama, Y. Oda, et al. Genotoxicity of 3,6-dinitrobenzo[e]pyrene, a novel mutagen in ambient air and surface soil, in mammalian cells in vitro and in vivo Mutagenesis, May 1, 2009; 24(3): 279 - 284. [Abstract] [Full Text] [PDF]

				J.-H. Choi, L. A. Lindsey-Boltz, and A. Sancar Cooperative activation of the ATR checkpoint kinase by TopBP1 and damaged DNA Nucleic Acids Res., April 1, 2009; 37(5): 1501 - 1509. [Abstract] [Full Text] [PDF]

				J. Baure, A. Izadi, V. Suarez, E. Giedzinski, J. E. Cleaver, J. R. Fike, and C. L. Limoli Histone H2AX phosphorylation in response to changes in chromatin structure induced by altered osmolarity Mutagenesis, March 1, 2009; 24(2): 161 - 167. [Abstract] [Full Text] [PDF]

				M. Wakasugi, H. Kasashima, Y. Fukase, M. Imura, R. Imai, S. Yamada, J. E. Cleaver, and T. Matsunaga Physical and functional interaction between DDB and XPA in nucleotide excision repair Nucleic Acids Res., February 1, 2009; 37(2): 516 - 525. [Abstract] [Full Text] [PDF]

				T. Stiff, K. Cerosaletti, P. Concannon, M. O'Driscoll, and P. A. Jeggo Replication independent ATR signalling leads to G2/M arrest requiring Nbs1, 53BP1 and MDC1 Hum. Mol. Genet., October 15, 2008; 17(20): 3247 - 3253. [Abstract] [Full Text] [PDF]

				K. Matsuura, M. Wakasugi, K. Yamashita, and T. Matsunaga Cleavage-mediated Activation of Chk1 during Apoptosis J. Biol. Chem., September 12, 2008; 283(37): 25485 - 25491. [Abstract] [Full Text] [PDF]

				S. Hanasoge and M. Ljungman H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is mediated by the ATR kinase Carcinogenesis, November 1, 2007; 28(11): 2298 - 2304. [Abstract] [Full Text] [PDF]

				J.-H. Choi, L. A. Lindsey-Boltz, and A. Sancar Reconstitution of a human ATR-mediated checkpoint response to damaged DNA PNAS, August 14, 2007; 104(33): 13301 - 13306. [Abstract] [Full Text] [PDF]

				L. A. Lindsey-Boltz and A. Sancar RNA polymerase: The most specific damage recognition protein in cellular responses to DNA damage? PNAS, August 14, 2007; 104(33): 13213 - 13214. [Full Text] [PDF]