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