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Pph3-Psy2 is a phosphatase complex required for Rad53 dephosphorylation and replication fork restart during recovery from DNA damage

Academic Article
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Overview

related to degree

  • Lis, Ewa Teresa, Ph.D. in Chemistry, Scripps Research 2002 - 2008
  • O'Neill, Bryan M, Ph.D. in Biology, Scripps Research 2001 - 2007

authors

  • O'Neill, Bryan M
  • Szyjka, S. J.
  • Lis, Ewa Teresa
  • Bailey, A. O.
  • Yates III, John
  • Aparicio, O. M.
  • Romesberg, Floyd

publication date

  • May 2007

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Activation of the checkpoint kinase Rad53 is a critical response to DNA damage that results in stabilization of stalled replication forks, inhibition of late-origin initiation, up-regulation of dNTP levels, and delayed entry to mitosis. Activation of Rad53 is well understood and involves phosphorylation by the protein kinases Mec1 and Tel1 as well as in trans autophosphorylation by Rad53 itself. However, deactivation of Rad53, which must occur to allow the cell to recover from checkpoint arrest, is not well understood. Here, we present genetic and biochemical evidence that the type 2A-like protein phosphatase Pph3 forms a complex with Psy2 (Pph3-Psy2) that binds and dephosphorylates activated Rad53 during treatment with, and recovery from, methylmethane sulfonate-mediated DNA damage. In the absence of Pph3-Psy2, Rad53 dephosphorylation and the resumption of DNA synthesis are delayed during recovery from DNA damage. This delay in DNA synthesis reflects a failure to restart stalled replication forks, whereas, remarkably, genome replication is eventually completed by initiating late origins of replication despite the presence of hyperphosphorylated Rad53. These findings suggest that Rad53 regulates replication fork restart and initiation of late firing origins independently and that regulation of these processes is mediated by specific Rad53 phosphatases.

subject areas

  • Cell Cycle Proteins
  • Checkpoint Kinase 2
  • DNA Damage
  • DNA Replication
  • DNA, Fungal
  • Enzyme Activation
  • Gene Expression Regulation, Fungal
  • Histones
  • Methyl Methanesulfonate
  • Nuclear Proteins
  • Phosphoprotein Phosphatases
  • Phosphorylation
  • Protein Binding
  • Protein-Serine-Threonine Kinases
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
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Research

keywords

  • YBL046W
  • cell cycle
  • checkpoint
  • phosphorylation
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Identity

PubMed Central ID

  • PMC1890487

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0703252104

PubMed ID

  • 17517611
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Additional Document Info

start page

  • 9290

end page

  • 9295

volume

  • 104

issue

  • 22

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