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

Journal Article · · Journal of Cell Biology
 [1];  [2];  [3];  [3];  [4];  [5]
  1. Columbia Univ., New York, NY (United States). Herbert Irving Comprehensive Cancer Center; DOE/OSTI
  2. Center for Radiological Research
  3. Columbia Univ., New York, NY (United States). Herbert Irving Comprehensive Cancer Center
  4. Columbia Univ., New York, NY (United States). Herbert Irving Comprehensive Cancer Center; Columbia Univ., New York, NY (United States). Center for Radiological Research; Columbia Univ., New York, NY (United States). Dept. of Environmental Health Science
  5. Columbia Univ., New York, NY (United States). Herbert Irving Comprehensive Cancer Center; Columbia Univ., New York, NY (United States). Dept. of Environmental Health Science; Columbia Univ., New York, NY (United States). Dept. of Medicine
+ Show Author Affiliations

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 γ-H2AX and ATM. HINT1 deficiency does not affect the formation of γ-H2AX foci; however, it impairs the removal of γ-H2AX foci after DNA damage and this is associated with impaired acetylation of γ-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 γ-H2AX and ATM.

Research Organization:
Columbia Univ., New York, NY (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
FG02-05ER64055
OSTI ID:
1625146
Journal Information:
Journal of Cell Biology, Journal Name: Journal of Cell Biology Journal Issue: 2 Vol. 183; ISSN 0021-9525
Publisher:
Rockefeller University PressCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (7)

Side Chain Independent Recognition of Aminoacyl Adenylates by the Hint1 Transcription Suppressor journal March 2012
The Axonal Motor Neuropathy-Related HINT1 Protein Is a Zinc- and Calmodulin-Regulated Cysteine SUMO Protease journal September 2019
SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair journal March 2019
FHIT overexpression in HepG2 hepatoma cells affects growth and cyclin D1 expression in vitro journal December 2013
Hint1 expression inhibits proliferation and promotes radiosensitivity of human SGC7901 gastric cancer cells journal June 2018
Opposing effects of HIF1α and HIF2α on chromaffin cell phenotypic features and tumor cell proliferation: Insights from MYC-associated factor X: Role of HIF1α and HIF2α in chromaffin cell development journal April 2014
Phosphoramidate hydrolysis catalyzed by human histidine triad nucleotide binding protein 1 (hHint1): a cluster-model DFT computational study journal January 2017

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Cell Biology