WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

Significance Genomic instability is a hallmark of human cancers. Common fragile sites (CFSs) pose nonrandom, preferential targets of genomic instability, such as chromosome breaks, in response to replicative stress. The tumor suppressor WW domain-containing oxidoreductase (WWOX) spans the CFS FRA16D and has been implicated in carcinogenesis by a currently unknown mechanism. In this study, we identify a direct role of WWOX in DNA damage response, which is a major antagonist of genomic instability. We show that WWOX maintains genomic stability and regulates DNA repair by modulating the activity of the DNA damage checkpoint kinase ataxia telangiectasia-mutated (ATM). Our findings provide evidence that a fragile gene product is directly involved in the response to DNA damage, suggesting a rationale for its preferential loss during carcinogenesis. Genomic instability is a hallmark of cancer. The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor spanning the common chromosomal fragile site FRA16D. Here, we report a direct role of WWOX in DNA damage response (DDR) and DNA repair. We show that Wwox deficiency results in reduced activation of the ataxia telangiectasia-mutated (ATM) checkpoint kinase, inefficient induction and maintenance of γ-H2AX foci, and impaired DNA repair. Mechanistically, we show that, upon DNA damage, WWOX accumulates in the cell nucleus, where it interacts with ATM and enhances its activation. Nuclear accumulation of WWOX is regulated by its K63-linked ubiquitination at lysine residue 274, which is mediated by the E3 ubiquitin ligase ITCH. These findings identify a novel role for the tumor suppressor WWOX and show that loss of WWOX expression may drive genomic instability and provide an advantage for clonal expansion of neoplastic cells.

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