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日時: 平成21年 12月 2日 (水曜日) 午後15:15 ~ 16:15

会場: (財)東京都医学研究機構 東京都臨床医学総合
研究所 2階会議室

演題:Revealing an ATM-to-ATR switch at DNA breaks using a novel in
vitro checkpoint activation assay (DNA損傷シグナル伝達機構の
in vitroシステムを用いた解析)

演者 :Bunsyo Shiotani博士 (Massachusetts General Hospital Cancer
Center

Harvard Medical School&s_comma; USA)



《要旨》

Double-strand DNA breaks (DSBs) activates DNA damage checkpoint kinase
ataxia telangiectasia (A-T) mutated (ATM) and A-T and RAD3-related
(ATR)&s_comma; which orchestrates the DNA damage response to delay cell cycle
progression and allow the repair of DNA damage. ATM is critical for
the initial response and the subsequent ATR activation. However&s_comma; the
structural determinant of DNA that activate ATM and ATR and how the
kinase activities are coordinated are poorly understood. Here we
showed that ATR activation is coupled with loss of ATM activation&s_comma; an
unexpected ATM-to-ATR switch during the biphasic DSB response. To
reveal the DNA structural determinants&s_comma; we developed an in vitro ATM/
ATR activation assay using human cell extracts and defined DNA
structures. ATM is activated by DSBs with blunts ends or short single-
strand overhangs (SSOs). Surprisingly&s_comma; the activation of ATM in the
presence of SSOs&s_comma; like that of ATR&s_comma; relies on single- and double-
stranded DNA junctions. In a length-dependent manner&s_comma; SSOs attenuate
ATM activation and potentiate ATR activation through a swap of DNA
damage sensors. Progressive resection of DSBs directly promotes the
ATM-to-ATR switch in vitro. In cells&s_comma; the ATM-to-ATR switch is driven
by both ATM and the nucleases participating in DSB resection. Thus&s_comma;
single-stranded DNA orchestrates ATM and ATR to function orderly and
reciprocally in two distinct phases of DSB response.



Bunsyo Shiotani and Lee Zou (2009) Single-Stranded DNA Orchestrates an
ATM-to-ATR Switch at DNA Breaks. Molecular Cell 33&s_comma; 547 558.



〔世話人:ゲノム動態プロジェクト 正井 久雄〕
Hisao Masai
Genome Dynamics Project&s_comma;
Tokyo Metropolitan Institute of Medical Science&s_comma;
2-1-6 Kamikitazawa&s_comma; Setagaya-ku&s_comma; Tokyo 156-8506&s_comma; JAPAN
Tel: 81-3-5316-3231 Fax: 81-3-5316-3145; E-mail: masai-hs@igakuken.or.jp
http://www.rinshoken.or.jp/CB/index-jp.htm

正井 久雄
東京都臨床医学総合研究所 ゲノム動態プロジェクト
郵便番号 156-8506
所在地  東京都世田谷区上北沢二丁目1番6号
正井直通電話 03-5316-3231
研究室電話 03-5316-3117
研究室FAX 03-5316-3145
E-mail masai-hs@igakuken.or.jp



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