The HINT1 tumor suppressor regulates both gamma-H2AX and ATM in response to DNA damage.
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 gamma-H2AX and ATM. HINT1 deficiency does not affect the formation of gamma-H2AX foci; however, it impairs the removal of gamma-H2AX foci after DNA damage and this is associated with impaired acetylation of gamma-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 gamma-H2AX and ATM.
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
Haiyang
H
Li
Adayabalam S
AS
Balajee
Tao
T
Su
Bo
B
Cen
Tom K
TK
Hei
I Bernard
IB
Weinstein
D000107:Acetylation / Q000528:radiation effects; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002869:Chromosome Aberrations / Q000528:radiation effects; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D005720:Gamma Rays; D005786:Gene Expression Regulation / Q000528:radiation effects; D042822:Genomic Instability / Q000528:radiation effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D011485:Protein Binding / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011995:Recombination, Genetic / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C489275:Hint1 protein, mouse; D006657:Histones; D009419:Nerve Tissue Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C475961:gamma-H2AX protein, mouse; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases