Functional activation of ATM by the prostate cancer suppressor NKX3.1

• Published in: Cell reports (Cambridge) Vol. 4; no. 3; pp. 516 - 529
• Main Authors: Bowen, Cai, Ju, Jeong-Ho, Lee, Ji-Hoon, Paull, Tanya T, Gelmann, Edward P
• Format: Journal Article
• Language: English
• Published: United States Elsevier 01-08-2013
• Subjects: Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; Cell Line, Tumor; DNA Damage; Gene Knockdown Techniques; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Male; Phosphorylation; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.06.039

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.