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Nucleic acids research
12 09, 2022;50 (22): 12844-12855.

Pif1 family helicases promote mutation avoidance during DNA replication.

Zhi-Xiong Zhou, Cindy Follonier, Scott A Lujan, Adam B Burkholder, Virginia A Zakian, Thomas A Kunkel
Author Information
  1. Zhi-Xiong Zhou: Genome Integrity & Structural Biology Laboratory, Princeton University, Princeton, NJ 08544, USA.
  2. Cindy Follonier: Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544, USA.
  3. Scott A Lujan: Genome Integrity & Structural Biology Laboratory, Princeton University, Princeton, NJ 08544, USA. ORCID
  4. Adam B Burkholder: Integrative Bioinformatics Support Group, NIH/NIEHS, DHHS, Research Triangle Park, NC 27709, USA.
  5. Virginia A Zakian: Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544, USA.
  6. Thomas A Kunkel: Genome Integrity & Structural Biology Laboratory, Princeton University, Princeton, NJ 08544, USA. ORCID
PMID: 36533450 DOI: 10.1093/nar/gkac1127

Abstract

Pif1 family 5' → 3' DNA helicases are important for replication fork progression and genome stability. The budding yeast Saccharomyces cerevisiae encodes two Pif1 family helicases, Rrm3 and Pif1, both of which are multi-functional. Here we describe novel functions for Rrm3 in promoting mutation avoidance during DNA replication. We show that loss of Rrm3 results in elevated spontaneous mutations made by DNA polymerases Pols ϵ and δ, which are subject to DNA mismatch repair. The absence of Rrm3 also causes higher mutagenesis by the fourth B-family DNA polymerase Pol ζ. By genome-wide analysis, we show that the mutational consequences due to loss of Rrm3 vary depending on the genomic locus. Rrm3 promotes the accuracy of DNA replication by Pols ϵ and δ across the genome, and it is particularly important for preventing Pol ζ-dependent mutagenesis at tRNA genes. In addition, mutation avoidance by Rrm3 depends on its helicase activity, and Pif1 serves as a backup for Rrm3 in suppressing mutagenesis. We present evidence that the sole human Pif1 family helicase in human cells likely also promotes replication fidelity, suggesting that a role for Pif1 family helicases in mutation avoidance may be evolutionarily conserved, a possible underlying mechanism for its potential tumor-suppressor function.

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Grants

  1. R35 GM118279/NIGMS NIH HHS
  2. Z01 ES065070/Intramural NIH HHS

MeSH Term

Humans
Cells, Cultured
Conserved Sequence
DNA Helicases
DNA Replication
Mutation
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins

Chemicals

DNA Helicases
PIF1 protein, human
PIF1 protein, S cerevisiae
Rrm3 protein, S cerevisiae
Saccharomyces cerevisiae Proteins
Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural
Article has an altmetric score of 1

Word Cloud

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