title: Functional activation of ATM by the prostate cancer suppressor NKX3.1.
abstract: The prostate tumor suppressor NKX3.1 augments response to DNA damage and enhances survival after DNA damage. Within minutes of DNA damage, NKX3.1 undergoes phosphorylation at tyrosine 222, which is required for a functional interaction with ataxia telangiectasia mutated (ATM) kinase. NKX3.1 binds to the N-terminal region of ATM, accelerates ATM activation, and hastens the formation of γhistone2AX. NKX3.1 enhances DNA-dependent ATM kinase activation by both the MRN complex and H2O2 in a DNA-damage-independent manner. ATM, bound to the NKX3.1 homeodomain, phosphorylates NKX3.1, leading to ubiquitination and degradation. Thus, NKX3.1 and ATM have a functional interaction leading to ATM activation and then NKX3.1 degradation in a tightly regulated DNA damage response specific to prostate epithelial cells. These findings demonstrate a mechanism for the tumor-suppressor properties of NKX3.1, demonstrate how NKX3.1 may enhance DNA integrity in prostate stem cells and may help to explain how cells differ in their sensitivity to DNA damage.
authors.affiliation: Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University, 177 Fort Washington Avenue, MHB 6N-435, New York, NY 10032, USA.
authors.forename: Cai
authors.initials: C
authors.lastname: Bowen
authors.forename: Jeong-Ho
authors.initials: JH
authors.lastname: Ju
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Lee
authors.forename: Tanya T
authors.initials: TT
authors.lastname: Paull
authors.forename: Edward P
authors.initials: EP
authors.lastname: Gelmann
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; C491178:NKX3-1 protein, human; D014157:Transcription Factors; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
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