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The HINT1 tumor suppressor regulates both -H2AX and ATM in response to DNA damage

¹ Herbert Irving Comprehensive Cancer Center, ² Center for Radiological Research, ³ Department of Environmental Health Science, and ⁴ Department of Medicine, Columbia University, New York, NY 10032

Correspondence to Bernard Weinstein: ibw1{at}columbia.edu

Hint1 is a haploinsufficient tumor suppressor gene and the underlying molecular mechanisms for its tumor suppressor function are unknown. In this study we demonstrate that HINT1 participates in ionizing radiation (IR)–induced DNA damage responses. In response to IR, HINT1 is recruited to IR-induced foci (IRIF) and associates with -H2AX and ATM. HINT1 deficiency does not affect the formation of -H2AX foci; however, it impairs the removal of -H2AX foci after DNA damage and this is associated with impaired acetylation of -H2AX. HINT1 deficiency also impairs acetylation of ATM and activation of ATM and its downstream effectors, and retards DNA repair, in response to IR. HINT1-deficient cells exhibit resistance to IR-induced apoptosis and several types of chromosomal abnormalities. Our findings suggest that the tumor suppressor function of HINT1 is caused by, at least in part, its normal role in enhancing cellular responses to DNA damage by regulating the functions of both -H2AX and ATM.

Abbreviations used in this paper: DDR, DNA damage responses; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; DSB, double strand breaks; IR, ionizing radiation; IRIF, Ionizing radiation-induced foci; MEF, mouse embryonic fibroblast; PFGE, pulse-field gel electrophoresis; shRNA, short hairpin RNA.

© 2008 Li et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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