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Mode of ATM-dependent suppression of chromosome translocation


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Title: Mode of ATM-dependent suppression of chromosome translocation
Authors: Yamauchi, Motohiro / Suzuki, Keiji / Oka, Yasuyoshi / Suzuki, Masatoshi / Kondo, Hisayoshi / Yamashita, Shunichi
Issue Date: 9-Dec-2011
Publisher: Elsevier Inc.
Citation: Biochemical and Biophysical Research Communications, 416(1-2), pp.111-118; 2011
Abstract: It is well documented that deficiency in ataxia telangiectasia mutated (ATM) protein leads to elevated frequency of chromosome translocation, however, it remains poorly understood how ATM suppresses translocation frequency. In the present study, we addressed the mechanism of ATM-dependent suppression of translocation frequency. To know frequency of translocation events in a whole genome at once, we performed centromere/telomere FISH and scored dicentric chromosomes, because dicentric and translocation occur with equal frequency and by identical mechanism. By centromere/telomere FISH analysis, we confirmed that chemical inhibition or RNAi-mediated knockdown of ATM causes 2 to 2.5-fold increase in dicentric frequency at first mitosis after 2. Gy of gamma-irradiation in G0/G1. The FISH analysis revealed that ATM/p53-dependent G1 checkpoint suppresses dicentric frequency, since RNAi-mediated knockdown of p53 elevated dicentric frequency by 1.5-fold. We found ATM also suppresses dicentric occurrence independently of its checkpoint role, as ATM inhibitor showed additional effect on dicentric frequency in the context of p53 depletion and Chk1/2 inactivation. Epistasis analysis using chemical inhibitors revealed that ATM kinase functions in the same pathway that requires kinase activity of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to suppress dicentric frequency. From the results in the present study, we conclude that ATM minimizes translocation frequency through its commitment to G1 checkpoint and DNA double-strand break repair pathway that requires kinase activity of DNA-PKcs.
Keywords: Ataxia telangiectasia mutated / Chromosome translocation / Dicentric
URI: http://hdl.handle.net/10069/27345
ISSN: 0006291X
DOI: 10.1016/j.bbrc.2011.11.006
Rights: Copyright © 2011 Elsevier Inc. All rights reserved.
Type: Journal Article
Text Version: author
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/27345

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