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APC/CCdh1-dependent proteolysis of USP1 regulates the response to UV-mediated DNA damage

Xiomaris M Cotto-Rios1, Mathew J K Jones, Luca Busino

  • 1Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA.

The Journal of Cell Biology
|July 20, 2011
PubMed

Insights

The anaphase-promoting complex/cyclosome(Cdh1) targets USP1 for destruction in G1, enabling DNA repair. This regulation of USP1 by APC/C(Cdh1) is crucial for genomic stability and UV damage response before DNA replication.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • The anaphase-promoting complex/cyclosome(Cdh1) (APC/C(Cdh1)) controls cell cycle progression by degrading key regulators.
  • Genomic stability and DNA repair are critical processes maintained by various cellular mechanisms.
  • Ubiquitin-specific protease 1 (USP1) is recognized for its role in DNA repair and maintaining genomic stability.

Purpose of the Study:

  • To investigate the role of APC/C(Cdh1) in regulating USP1 during the G1 phase.
  • To elucidate the impact of USP1 degradation on DNA repair pathways, particularly in response to UV damage.
  • To understand the mechanism by which APC/C(Cdh1)-mediated USP1 degradation influences proliferating cell nuclear antigen (PCNA) monoubiquitination.

Main Methods:

  • Utilizing cell cycle synchronization techniques to isolate the G1 phase.
  • Employing biochemical assays to detect and quantify protein degradation via APC/C(Cdh1).
  • Generating and analyzing USP1 mutants resistant to APC/C(Cdh1) degradation.
  • Assessing PCNA monoubiquitination status and trans-lesion synthesis polymerase recruitment following UV irradiation.

Main Results:

  • USP1 is identified as a novel substrate degraded by APC/C(Cdh1) during the G1 phase.
  • Low USP1 levels in G1 are essential for efficient PCNA monoubiquitination upon UV damage.
  • A non-degradable USP1 mutant impairs PCNA monoubiquitination, suggesting compromised DNA repair.
  • APC/C(Cdh1)-mediated USP1 degradation facilitates the recruitment of repair polymerases to UV-induced DNA lesions.

Conclusions:

  • APC/C(Cdh1) plays a critical role in regulating USP1 levels during G1, contributing to genomic stability.
  • The degradation of USP1 by APC/C(Cdh1) is a key event that permits PCNA monoubiquitination and subsequent DNA repair before S phase entry.
  • This mechanism highlights a novel link between cell cycle control and DNA damage response pathways, specifically involving USP1 and PCNA.

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