VGLL3 modulates chemosensitivity through promoting DNA double-strand break repair

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• Transcription cofactor vestigial-like 3 (VGLL3) regulates autoimmunity and tumor development.
• The precise mechanisms of VGLL3 in these processes are not fully understood.

Purpose of the Study:

• To investigate the role of VGLL3 in DNA damage response (DDR).
• To elucidate the molecular mechanisms by which VGLL3 influences DDR and homologous recombination.

Main Methods:

• Investigated VGLL3 recruitment to DNA damage sites.
• Assessed the impact of VGLL3 depletion on DNA repair protein accumulation (RNF8, RAD51).
• Analyzed homologous recombination efficiency and cellular sensitivity to chemotherapeutic drugs.
• Examined protein-protein interactions involving VGLL3, KLHL15, CtIP, MDC1, TRIP12, and USP7.

Main Results:

• VGLL3 is recruited to DNA damage sites via PARylation.
• VGLL3 depletion reduces RNF8 and RAD51 accumulation at damage sites, impairing homologous recombination.
• VGLL3 stabilizes MDC1 and prevents CtIP degradation, facilitating RNF8 signaling.
• VGLL3 depletion delays tumor growth and increases sensitivity to etoposide in xenografts.

Conclusions:

• VGLL3 plays a novel, non-transcriptional role in DNA damage response.
• VGLL3 is essential for efficient homologous recombination repair.
• VGLL3's function in DDR is distinct from its known transcriptional cofactor activity and not conserved across VGLL family members.