Activation of the Cellular DNA Damage Response in the Absence of DNA Lesions
Abstract
The cellular DNA damage response (DDR) is initiated by the rapid recruitment of repair factors to the site of DNA damage to form a multiprotein repair complex. How the repair complex senses damaged DNA and then activates the DDR is not well understood. We show that prolonged binding of DNA repair factors to chromatin can elicit the DDR in an ATM (ataxia telangiectasia mutated)– and DNAPK (DNA-dependent protein kinase)–dependent manner in the absence of DNA damage. Targeting of single repair factors to chromatin revealed a hierarchy of protein interactions within the repair complex and suggests amplification of the damage signal. We conclude that activation of the DDR does not require DNA damage and stable association of repair factors with chromatin is likely a critical step in triggering, amplifying, and maintaining the DDR signal.
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We thank J. Lukas and Y. Shiloh for reagents and comments; A. Belmont, T. Paull, and M. Kastan for reagents; S. Snyder for technical assistance; and M. Kruhlak for help with microscopy. Imaging was performed at the National Cancer Institute (NCI) Fluorescence Imaging Facility. E.S. was supported by a fellowship from the Human Frontier Science Program. This research was supported by the Intramural Research Program of the NIH, NCI, and Center for Cancer Research.
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Science
Volume 320 | Issue 5882
13 June 2008
13 June 2008
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American Association for the Advancement of Science.
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Received: 14 April 2008
Accepted: 1 May 2008
Published in print: 13 June 2008
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