Pif1 family helicases promote mutation avoidance during DNA replication. Issue 22 (19th December 2022)

• Record Type: Journal Article
• Authors: Zhou, Zhi-Xiong; Follonier, Cindy; Lujan, Scott A; Burkholder, Adam B; Zakian, Virginia A; Kunkel, Thomas A
• Is Part Of: Nucleic acids research. Volume 50:Issue 22(2022)
• Page Start: 12844
• Page End: 12855
• Publication Date: 2022-12-19
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkac1127
• Languages: English
• ISSNs: 0305-1048

Abstract

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.