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UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability

Sabrina F Mansilla1, Gastón Soria, María Belén Vallerga

  • 1Cell Cycle and Genomic Stability Laboratory, Fundación Instituto Leloir-CONICET, Buenos Aires C1405BWE, Argentina.

Nucleic Acids Research
|June 1, 2013
PubMed

Insights

UV irradiation triggers p21 degradation to prevent DNA replication defects. Stabilizing p21 after UV impairs DNA repair by blocking Y-family polymerases, leading to genomic instability. Degradation allows normal DNA repair and genomic stability.

Area of Science:

  • Molecular Biology
  • DNA Repair Mechanisms
  • Cellular Response to DNA Damage

Background:

  • Genotoxic treatments, including UV irradiation, often upregulate the cyclin-dependent kinase inhibitor p21.
  • However, UV irradiation paradoxically triggers p21 degradation, suggesting p21 inhibits a crucial UV response pathway.
  • Understanding p21's role in UV response is vital for comprehending cellular defense against DNA damage.

Purpose of the Study:

  • To investigate the role of p21 stabilization versus degradation in the cellular response to UV-induced DNA damage.
  • To elucidate the mechanism by which p21 affects DNA replication and genomic stability following UV exposure.
  • To determine if p21's interaction with PCNA is critical for its function in UV response.

Main Methods:

  • Forced stabilization of p21 in cells post-UV irradiation.
  • Disruption of the proliferating cell nuclear antigen (PCNA) interacting motif of p21.
  • Assessment of damaged-DNA replication, Y-family DNA polymerase recruitment, DNA damage markers, and genomic instability.
  • Comparison of outcomes between stable p21, degradable p21, and disrupted p21 variants.

Main Results:

  • Forced p21 stabilization after UV irradiation significantly impaired damaged-DNA replication and Y-family polymerase recruitment, leading to increased DNA damage markers and genomic instability.
  • Disrupting the PCNA-interacting motif of stabilized p21 abolished these detrimental effects, indicating PCNA interaction is key.
  • Transiently expressed degradable p21 caused only temporary delays in replication and polymerase recruitment, with no lasting genomic consequences.

Conclusions:

  • UV-triggered p21 degradation is essential for preventing replication defects and maintaining genomic stability.
  • p21 degradation facilitates the recruitment of Y-family polymerases to PCNA, enabling translesion DNA synthesis and tolerance of UV-induced DNA lesions.
  • The controlled degradation of p21 is a critical regulatory mechanism for efficient DNA repair and cellular survival after UV exposure.

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