WWOX modulates the ATR-mediated DNA damage checkpoint response

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• Genomic instability is a key characteristic of cancer.
• The tumor suppressor WWOX (WW domain-containing oxidoreductase) is known to be involved in DNA double-strand break responses.
• Its role in DNA single-strand break (SSB) responses remains largely unexplored.

Purpose of the Study:

• To investigate the novel functions of WWOX in the DNA single-strand break (SSB) checkpoint activation.
• To elucidate the molecular mechanisms underlying WWOX's role in DNA damage response.

Main Methods:

• Analysis of WWOX expression and localization following SSBs.
• Assessment of checkpoint protein activation (ATR, ATM) in WWOX-deficient cells.
• Investigation of WWOX post-translational modifications (ubiquitination) and protein interactions (ITCH, ATM).

Main Results:

• WWOX levels increase and it accumulates in the nucleus upon SSBs.
• WWOX deficiency leads to reduced ataxia telangiectasia and Rad3-related protein (ATR) activation and increased chromosomal breaks.
• WWOX is ubiquitinated by ITCH at lysine 274 and interacts with ataxia telangiectasia-mutated (ATM); ATR activation is ATM-dependent.

Conclusions:

• WWOX plays a critical role in activating the ATR-mediated DNA single-strand break checkpoint.
• WWOX deficiency contributes to genomic instability by compromising the SSB DNA damage response.
• These findings reveal new functions for WWOX in maintaining genome integrity.