Abstract
For many decades genomic instability is considered one of the hallmarks of cancer. Role of the tumor suppressor WWOX (WW domain-containing oxidoreductase) in DNA damage response upon double strand breaks has been recently revealed. Here we demonstrate unforeseen functions for WWOX upon DNA single strand breaks (SSBs) checkpoint activation. We found that WWOX levels are induced following SSBs and accumulate in the nucleus. WWOX deficiency is associated with reduced activation of ataxia telangiectasia and Rad3-related protein (ATR) checkpoint proteins and increased chromosomal breaks. At the molecular level, we show that upon SSBs WWOX is modified at lysine 274 by ubiquitination mediated by the ubiquitin E3 ligase ITCH and interacts with ataxia telangiectasia-mutated (ATM). Interestingly, ATM inhibition was associated with reduced activation of ATR checkpoint proteins suggesting that WWOX manipulation of ATR checkpoint proteins is ATM-dependent. Taken together, the present findings indicate that WWOX plays a key role in ATR checkpoint activation, while its absence might facilitate genomic instability.
Highlights
Genomic instability, one of the cancer hallmarks, plays critical roles both in tumor initiation and progression
We showed that WW domaincontaining oxidoreductase (WWOX) levels are induced upon HU, UVC and APH treatment, likely due to protein ubiquitination-mediated by ITCH
Emerging findings support the function of WWOX as a tumor suppressor: (i) overexpression of WWOX in WWOX-negative cancer cells reduces cell growth and suppresses tumor growth in immunodeficient mice [36,37,38]; (ii) Wwox-mutant mice showed higher incidence of spontaneous and chemicallyinduced tumors [39, 40]; (iii) WWOX molecularly regulates several cellular processes implicated in tumor initiation and/or progression [37, 41]
Summary
One of the cancer hallmarks, plays critical roles both in tumor initiation and progression. It is characterized by accumulation of chromosomal changes ranging from mutations within the DNA sequence to structural abnormalities [1]. In eukaryotic cells the most common causes of genomic instability are failure of DNA replication and DNA-damage response (DDR), which are increased by external genotoxic agents and/or cellular pathologies [2]. The cells can use a repertoire of repair mechanisms during all stages of the cell cycle to preserve the genome from the mutagenic action of genotoxic agents and to guarantee faithful chromosome duplication and transmission to the daughter cells [3]. Upon a severe damage the cells are facing the fatedecision: to undergo apoptosis or senescence or to live with mutated genome [5]
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