Abu-Odeh Mohammad, Salah Zaidoun, Herbel Christoph, Hofmann Thomas G, Aqeilan Rami I
The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research-Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel;
The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research-Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; Al Quds-Bard College, Al-Quds University, Abu Dies, East Jerusalem; and.
Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):E4716-25. doi: 10.1073/pnas.1409252111. Epub 2014 Oct 20.
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.
基因组不稳定是癌症的一个标志。含WW结构域的氧化还原酶（WWOX）是一种肿瘤抑制因子，跨越常见的染色体脆性位点FRA16D。在此，我们报道了WWOX在DNA损伤反应（DDR）和DNA修复中的直接作用。我们发现Wwox缺陷导致共济失调毛细血管扩张突变（ATM）检查点激酶的激活减少、γ-H2AX焦点的诱导和维持效率低下以及DNA修复受损。从机制上讲，我们表明，在DNA损伤时，WWOX在细胞核中积累，在那里它与ATM相互作用并增强其激活。WWOX的核积累由其赖氨酸残基274处的K63连接泛素化调节，这是由E3泛素连接酶ITCH介导的。这些发现确定了肿瘤抑制因子WWOX的新作用，并表明WWOX表达缺失可能导致基因组不稳定，并为肿瘤细胞的克隆扩增提供优势。
