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The inner workings of replisome-dependent control of DNA damage tolerance

Tianpeng Zhang1, Roger A Greenberg1

  • 1Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Genes & Development
|February 23, 2022
PubMed

Insights

DNA replication forks use histone deposition to promote template switch (TS) repair and suppress error-prone translesion synthesis (TLS). This mechanism maintains genome integrity and impacts cancer therapy response.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Genomic DNA faces constant damage from internal and external factors.
  • DNA lesions can halt DNA replication, requiring specialized repair pathways.
  • DNA damage tolerance (DDT) pathways, including translesion synthesis (TLS) and template switch (TS), enable replication to bypass DNA lesions.

Purpose of the Study:

  • To elucidate how the DNA replisome regulates the choice between different DNA damage tolerance (DDT) repair mechanisms at replication blocks.
  • To investigate the role of parental histone deposition by replisome components in orchestrating DDT pathway activation.

Main Methods:

  • Investigated the roles of Ctf4 and Dpb3/4, components of the DNA replisome.
  • Utilized genetic deletion strategies (ctf4Δ, Dpb3/4 deletion) to assess cellular responses to DNA-damaging agents.
  • Analyzed mutagenesis rates to evaluate the balance between TLS and TS repair.

Main Results:

  • Parental histone deposition by Ctf4 and Dpb3/4 promotes template switch (TS) repair.
  • These histone deposition activities suppress error-prone translesion synthesis (TLS).
  • Deletion of Dpb3/4 in ctf4Δ cells restored DNA damage resistance but increased mutagenesis due to elevated TLS.

Conclusions:

  • Replisome-directed chromatin maintenance is crucial for preserving genome integrity.
  • The balance between TS and TLS is regulated by replisome components and histone deposition.
  • Understanding these mechanisms is vital for developing effective DNA-damaging anticancer therapeutics.
Keywords:
DNA damage toleranceDpb3–Dpb4Mcm2–Ctf4–Polαhistone depositionmutagenesisrecombinationreplication fork

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