title: NKX3.1 Suppresses TMPRSS2-ERG Gene Rearrangement and Mediates Repair of Androgen Receptor-Induced DNA Damage.
abstract: TMPRSS2 gene rearrangements occur at DNA breaks formed during androgen receptor-mediated transcription and activate expression of ETS transcription factors at the early stages of more than half of prostate cancers. NKX3.1, a prostate tumor suppressor that accelerates the DNA repair response, binds to androgen receptor at the ERG gene breakpoint and inhibits both the juxtaposition of the TMPRSS2 and ERG gene loci and also their recombination. NKX3.1 acts by accelerating DNA repair after androgen-induced transcriptional activation. NKX3.1 influences the recruitment of proteins that promote homology-directed DNA repair. Loss of NKX3.1 favors recruitment to the ERG gene breakpoint of proteins that promote error-prone nonhomologous end-joining. Analysis of prostate cancer tissues showed that the presence of a TMPRSS2-ERG rearrangement was highly correlated with lower levels of NKX3.1 expression consistent with the role of NKX3.1 as a suppressor of the pathogenic gene rearrangement.
authors.affiliation: Department of Medicine, Columbia University, Herbert Irving Comprehensive Cancer Center, New York, New York.
authors.forename: Cai
authors.initials: C
authors.lastname: Bowen
authors.affiliation: Department of Statistics, Columbia University, Herbert Irving Comprehensive Cancer Center, New York, New York.
authors.forename: Tian
authors.initials: T
authors.lastname: Zheng
authors.affiliation: Department of Medicine, Columbia University, Herbert Irving Comprehensive Cancer Center, New York, New York. Department of Pathology, Columbia University, Herbert Irving Comprehensive Cancer Center, New York, New York. gelmanne@columbia.edu.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Gelmann
mesh_terms: D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D015321:Gene Rearrangement; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D015533:Transcriptional Activation; D000071230:Transcriptional Regulator ERG
chemical_list: C410798:AR protein, human; C072312:ERG protein, human; D018398:Homeodomain Proteins; C491178:NKX3-1 protein, human; D011944:Receptors, Androgen; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human