Getting it done at the ends: Pif1 family DNA helicases and telomeres

Abstract

It is widely appreciated that the ends of linear DNA molecules cannot be fully replicated by the conventional replication apparatus. Less well known is that semi-conservative replication of telomeric DNA also presents problems for DNA replication. These problems likely arise from the atypical chromatin structure of telomeres, the GC-richness of telomeric DNA that makes it prone to forming DNA secondary structures, and from RNA-DNA hybrids, formed by transcripts of one or both DNA strands. Given the different aspects of telomeres that complicate their replication, it is not surprising that multiple DNA helicases promote replication of telomeric DNA. This review focuses on one such class of DNA helicases, the Pif1 family of 5′–3′ DNA helicases. In budding and fission yeasts, Pif1 family helicases impact both telomerase-mediated and semi-conservative replication of telomeric DNA as well as recombination-mediated telomere lengthening.

Mechanistic and biological considerations of oxidatively damaged DNA for helicase-dependent pathways of nucleic acid metabolism

“…Beyond the response to oxidative stress, yeast PIF1 is known to have essential roles at chromosome ends (telomeres), ribosomal DNA maintenance, and Okazaki fragment processing (for review, see [184–186]). With advances pointing toward an important role of Pif1 in nuclear as well as mitochondrial DNA metabolism in yeast, Futami et al first reported the localization of human Pif1 in mitochondria as well as nuclei [187].…”

“…This area seems to be greatly understudied, and we anxiously await progress to learn if Pif1 modulates 5’ flap processing during BER in the mitochondria where oxidative stress is prominent. This seems a reasonable possibility, as a number of studies indicate a role of Pif1 in Okazaki fragment processing and telomere maintenance by virtue of its ability to efficiently unwind 5’ flap DNA structures, a key intermediate of long patch BER, as mentioned above (for review, see [184–186]). Given that predicted G4 DNA structures believed to impede DNA synthesis are abundant in eukaryotic nuclear and mitochondrial genomes [188–192], it seems probable that PIF1 plays an important role to resolve such mtDNA structures in human cells, as evidence already implicates the homolog in nuclear DNA replication through G4 sequences in S. cerevisiae [193] and S. pombe [9].…”

PIF1 family DNA helicases suppress R-loop mediated genome instability at tRNA genes

“…These structures include stable protein complexes, highly transcribed genes and stable DNA secondary structures1. Paused replication forks are particularly susceptible to breakage owing to the single-stranded DNA at the fork.…”

Close encounters: Moving along bumps, breaks, and bubbles on expanded trinucleotide tracts

“…In the engineered yeast system harboring large CAG expansions [185], loss of Rad51, Rad52, Mre11, Pif1, and Mus81 and/or Yen1 proteins suppressed TNR expansion, all of which are proteins of BIR and recombination pathways [183,184]. Pif1 prevents replication- fork stalling at G-quadruplexes [186]. The factors that promote expansion are members of the recombination machinery.…”