The Caenorhabditis elegans Werner syndrome protein functions upstream of ATR and ATM in response to DNA replication inhibition and double-strand DNA breaks

PLoS Genet. 2010 Jan;6(1):e1000801. doi: 10.1371/journal.pgen.1000801. Epub 2010 Jan 8.

Abstract

WRN-1 is the Caenorhabditis elegans homolog of the human Werner syndrome protein, a RecQ helicase, mutations of which are associated with premature aging and increased genome instability. Relatively little is known as to how WRN-1 functions in DNA repair and DNA damage signaling. Here, we take advantage of the genetic and cytological approaches in C. elegans to dissect the epistatic relationship of WRN-1 in various DNA damage checkpoint pathways. We found that WRN-1 is required for CHK1 phosphorylation induced by DNA replication inhibition, but not by UV radiation. Furthermore, WRN-1 influences the RPA-1 focus formation, suggesting that WRN-1 functions in the same step or upstream of RPA-1 in the DNA replication checkpoint pathway. In response to ionizing radiation, RPA-1 focus formation and nuclear localization of ATM depend on WRN-1 and MRE-11. We conclude that C. elegans WRN-1 participates in the initial stages of checkpoint activation induced by DNA replication inhibition and ionizing radiation. These functions of WRN-1 in upstream DNA damage signaling are likely to be conserved, but might be cryptic in human systems due to functional redundancy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans / radiation effects
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Checkpoint Kinase 1
  • DNA Breaks, Double-Stranded* / radiation effects
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • DNA Repair
  • DNA Replication*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Disease Models, Animal
  • Down-Regulation
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Gamma Rays
  • Humans
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Replication Protein A / genetics
  • Replication Protein A / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ultraviolet Rays
  • Werner Syndrome / genetics
  • Werner Syndrome / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Replication Protein A
  • RpA-70 protein, Drosophila
  • Tumor Suppressor Proteins
  • Protein Kinases
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Mei-41 protein, Drosophila
  • Protein-Serine-Threonine Kinases
  • DNA Helicases
  • WRN-1 protein, C elegans