Dynamic regulation of Pif1 acetylation is crucial to the maintenance of genome stability
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MINI-REVIEW
Dynamic regulation of Pif1 acetylation is crucial to the maintenance of genome stability Onyekachi E. Ononye1 · Christopher W. Sausen2 · Matthew L. Bochman2 · Lata Balakrishnan1 Received: 2 October 2020 / Revised: 2 October 2020 / Accepted: 9 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract PIF1 family helicases are evolutionarily conserved among prokaryotes and eukaryotes. These enzymes function to support genome integrity by participating in multiple DNA transactions that can be broadly grouped into DNA replication, DNA repair, and telomere maintenance roles. However, the levels of PIF1 activity in cells must be carefully controlled, as Pif1 over-expression in Saccharomyces cerevisiae is toxic, and knockdown or over-expression of human PIF1 (hPIF1) supports cancer cell growth. This suggests that PIF1 family helicases must be subject to tight regulation in vivo to direct their activities to where and when they are needed, as well as to maintain those activities at proper homeostatic levels. Previous work shows that C-terminal phosphorylation of S. cerevisiae Pif1 regulates its telomere maintenance activity, and we recently identified that Pif1 is also regulated by lysine acetylation. The over-expression toxicity of Pif1 was exacerbated in cells lacking the Rpd3 lysine deacetylase, but mutation of the NuA4 lysine acetyltransferase subunit Esa1 ameliorated this toxicity. Using recombinant proteins, we found that acetylation stimulated the DNA binding affinity, ATPase activity, and DNA unwinding activities of Pif1. All three domains of the helicase were targets of acetylation in vitro, and multiple lines of evidence suggest that acetylation drives a conformational change in the N-terminal domain of Pif1 that impacts this stimulation. It is currently unclear what triggers lysine acetylation of Pif1 and how this modification impacts the many in vivo functions of the helicase, but future work promises to shed light on how this protein is tightly regulated within the cell. Keywords Pif1 helicase · Lysine acetylation · DNA replication · DNA repair · G4 resolvase · NuA4 (Esa1) · Rpd3
Introduction The Petite Integration Frequency 1 (PIF1) gene was identified in 1983 during a screen for mutants that disrupt mitochondrial DNA recombination in the budding yeast Saccharomyces cerevisiae (Foury and Kolodynski 1983). A decade later, the Pif1 gene product was purified and shown to have single-stranded DNA (ssDNA)-dependent ATPase and 5ʹ-3ʹ Communicated by M. Kupiec. * Matthew L. Bochman [email protected] * Lata Balakrishnan [email protected] 1
Department of Biology, School of Science, Indiana University Purdue University Indianapolis, Indianapolis, USA
Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, USA
2
DNA helicase activities (Lahaye, et al. 1993, 1991). Little did the field know that this yeast enzyme was the founding member of the PIF1 family of multifunctional DNA helicases found in both prokaryotes and eukaryotes (Bochman et a
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