Abstract

The two PIF1 family helicases in Saccharomyces cerevisiae, Rrm3, and ScPif1, associate with thousands of sites throughout the genome where they perform overlapping and distinct roles in telomere length maintenance, replication through non-histone proteins and G4 structures, lagging strand replication, replication fork convergence, the repair of DNA double-strand break ends, and transposable element mobility. ScPif1 and its fission yeast homolog Pfh1 also localize to mitochondria where they protect mitochondrial genome integrity. In addition to yeast serving as a model system for the rapid functional evaluation of human Pif1 variants, yeast cells lacking Rrm3 have proven useful for elucidating the cellular response to replication fork pausing at endogenous sites. Here, we review the increasingly important cellular functions of the yeast PIF1 helicases in maintaining genome integrity, and highlight recent advances in our understanding of their roles in facilitating fork progression through replisome barriers, their functional interactions with DNA repair, and replication stress response pathways.

Highlights

  • The two PIF1 family helicases in Saccharomyces cerevisiae, Rrm3, and ScPif1, associate with thousands of sites throughout the genome where they perform overlapping and distinct roles in telomere length maintenance, replication through non-histone proteins and G4 structures, lagging strand replication, replication fork convergence, the repair of DNA double-strand break ends, and transposable element mobility

  • Though unresolved G4 structures act as barriers to DNA replication and can cause genome instability, sequences capable of adopting G4 structures are enriched at human origins of replication, gene promoters, telomeres, as well as in ribosomal DNA (rDNA) and the mitochondrial genome, suggestive of a functional role

  • In contrast to rrm3∆-sensitive fragile sites that are caused by impeded replication forks encountering non-nucleosomal DNA-bound proteins, fragile site expression in RSZs is the result of depletion of the dNTP pool [178], suggesting that two types of fragile sites exist within the yeast genome: dNTP-sensitive (RSZ) and rrm3-sensitive

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Summary

History of the PIF1 DNA Helicase Family

The PIF1 DNA helicase family is conserved from bacteria to mammals [1,2]. While the yeast. DNA recombination mutation 3 (RRM3) gene was identified and later classified as a member of the PIF1 DNA helicase family based on sequence similarity [4,5]. Both Rrm and ScPif belong to the superfamily 1B and have 50 –30 translocase activity that is encoded in helicase domains that share 40%. N-terminal extensions of Rrm and ScPif to regulate their enzymatic activity and their recruitment to specific sites within the yeast genome, where they perform the many distinct cellular functions discussed in this review

Structure andand functional yeastand andhuman human
Replication
Physical
Termination
Telomere Length Maintenance
Okazaki Fragment Maturation
Resolution of G4 Structures
Cellular Response to Replication Fork Stalling in the Absence of Rrm3
A Helicase-Independent Function of Rrm3 During Replication Stress
10. Protection of Mitochondrial DNA
11. Localization to Centromeres
12. DNA Break Repair
13. Regulation of Ty1 Transposition
14. Fragile Site Expression
15. Yeast as a Model System for the Functional Evaluation of hPif1 Mutations
16. Concluding Remarks
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