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DNA damage tolerance in stem cells, ageing, mutagenesis, disease and cancer therapy

Bas Pilzecker1, Olimpia Alessandra Buoninfante1, Heinz Jacobs1

  • 1Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

Nucleic Acids Research
|June 29, 2019
PubMed

Insights

DNA damage tolerance (DDT) allows cells to replicate DNA despite damage, preventing genome instability and mutations. This review explores DDT

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • The genome is constantly challenged by DNA damage from internal and external sources.
  • The DNA damage response network is crucial for maintaining genomic integrity.
  • DNA damage tolerance (DDT) is a key mechanism enabling replication fork progression during DNA damage.

Purpose of the Study:

  • To provide an overview of DNA damage tolerance (DDT) mechanisms.
  • To highlight the role of DDT in genome stability, mutagenesis, and cellular fitness.
  • To discuss the implications of DDT in stem cell maintenance, aging, and cancer prevention.

Main Methods:

  • This review synthesizes existing research on DNA damage tolerance.
  • It categorizes DDT into four principal modes: translesion synthesis, fork reversal, template switching, and repriming.
  • The review discusses how these mechanisms prevent secondary DNA damage and fork collapse.

Main Results:

  • DNA damage tolerance (DDT) encompasses multiple pathways that allow replication to proceed past DNA lesions or structural impediments.
  • Effective DDT prevents fork arrest, fork collapse, and the formation of DNA double-strand breaks.
  • Four main DDT modes ensure replication continuation by bypassing or resolving stalling impediments.

Conclusions:

  • DNA damage tolerance (DDT) is essential for maintaining genome stability and cellular health.
  • Dysfunctional DDT can lead to genomic instability, contributing to aging and cancer.
  • Understanding DDT mechanisms is vital for research in mutagenesis, stem cell biology, and oncology.

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