Genomic instability is a hallmark of cancer. The WW domaincontaining
oxidoreductase (WWOX) is a tumor suppressor spanning
the common chromosomal fragile site FRA16D. Here, we report a
direct role ofWWOXin 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 instabilityWe thank Dr. Eugenio Gaudio and Dr. Sonja Matt for
technical help, Dr. Yossi Shiloh for the ataxia telangiectasia-mutated inhibitor,
and Dr. Kay Huebner for the rabbit polyclonal WW domaincontaining
oxidoreductase antibody. This study was supported by a German
Israeli Foundation Joint Grant (to T.G.H. and R.I.A.), Israeli Cancer Research
Funds (to Z.S. and R.I.A.), Deutsche Forschungsgemeinschaft Grant SFB1036
(to T.G.H.), and the Deutsche Krebshilfe (T.G.H.)