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Endogenous p21 levels protect genomic stability by suppressing both excess and restrained nascent DNA syntheses

Nicolás L Calzetta1, Sabrina F Mansilla1, Candelaria Mares Ahlers1

  • 1Fundación Instituto Leloir (IIBBA-CONICET), Buenos Aires, Argentina.

Science Advances
|October 8, 2025
PubMed

Insights

Endogenous p21 levels regulate DNA synthesis rates and genomic stability. Insufficient p21 promotes instability by enabling alternative DNA polymerases, while sufficient p21 prevents this through PCNA binding.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • DNA synthesis rate is vital for complete DNA duplication.
  • p21 plays a critical role in regulating DNA synthesis and maintaining genomic stability.
  • The function of p21 in DNA replication is complex and context-dependent.

Purpose of the Study:

  • To elucidate the role of p21 in controlling the rate of nascent DNA synthesis.
  • To investigate how different levels of p21 affect DNA replication pathways.
  • To understand the link between p21 expression, DNA synthesis, and chromosomal instability.

Main Methods:

  • Assessing nascent DNA synthesis rates under varying p21 expression levels.
  • Investigating the involvement of DNA polymerases (Pol ι, PrimPol, Pol κ) and p53.
  • Analyzing the impact of p21 on chromosomal stability in different cellular contexts, including p53-null cells.

Main Results:

  • p21 promotes nascent DNA synthesis with Pol ι/p53 complex during normal replication.
  • Down-regulated p21 leads to longer, discontinuous DNA synthesis mediated by PrimPol.
  • Complete p21 elimination results in shorter, continuous DNA synthesis dependent on Pol κ.
  • Both PrimPol- and Pol κ-mediated syntheses can induce chromosomal instability.
  • Residual p21 in p53-null cells influences PrimPol/Pol κ involvement and subsequent instability.

Conclusions:

  • Endogenous p21 levels, even below CDK inhibitory thresholds, are crucial for preventing genomic instability.
  • p21 prevents genomic instability by binding PCNA, thereby limiting the roles of PrimPol and Pol κ in nascent DNA synthesis.
  • These findings highlight p21 as a key regulator of DNA replication fidelity and genomic integrity.

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