USP37 regulates DNA damage response through stabilizing and deubiquitinating BLM.

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• The BLM helicase is essential for DNA repair and genomic stability, and its dysfunction causes Bloom syndrome.
• Mechanisms regulating BLM in cancer are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanism regulating BLM stability and function in the DNA damage response.
• To investigate the role of USP37 in BLM regulation and its implications in cancer.

Main Methods:

• Co-immunoprecipitation to assess protein interactions.
• Western blotting to detect protein levels and ubiquitination.
• Cell-based assays to evaluate DNA damage response and sensitivity to genotoxic agents.
• In vivo mouse models to validate findings.

Main Results:

• USP37 interacts with and deubiquitinates BLM, stabilizing the helicase.
• DNA double-strand breaks induce ATM-mediated phosphorylation of USP37, enhancing its binding to BLM.
• USP37 knockdown leads to increased BLM polyubiquitination, proteolysis, and impaired DNA damage response.
• Reduced USP37 sensitizes breast cancer cells to DNA-damaging agents in vitro and in vivo.

Conclusions:

• The USP37-BLM axis represents a novel regulatory mechanism for DNA double-strand break repair.
• This pathway plays a critical role in the response to chemotherapy and radiotherapy in human cancers.