WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response
WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response
Date
2014-10-20
Authors
Abu-Odeh, Mohammad
Salah, Zaidoun
Herbel, Christoph
Hofmann, Thomas G.
Aqeilan, Rami I.
Journal Title
Journal ISSN
Volume Title
Publisher
National Academy of Sciences
Abstract
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 instability