The Caenorhabditis elegans Werner Syndrome Protein functions upstream of ATR and ATM in response to DNA Replication Inhibition and Double-Strand DNA Breaks

TY - JOUR

T1 - The Caenorhabditis elegans Werner Syndrome Protein functions upstream of ATR and ATM in response to DNA Replication Inhibition and Double-Strand DNA Breaks

AU - Lee, Se-Jin

AU - Gartner, Anton

AU - Hyun, Moonjung

AU - Ahn, Byungchan

AU - Koo, Hyeon-Sook

PY - 2010/1

Y1 - 2010/1

N2 - 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.

AB - 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.

KW - C-ELEGANS

KW - DAMAGE CHECKPOINT

KW - INDUCED APOPTOSIS

KW - SYNDROME HELICASE

KW - RECQ HELICASE

KW - LIFE-SPAN

KW - S-PHASE

KW - EXONUCLEASE

KW - ACTIVATION

KW - PHOSPHORYLATION

U2 - 10.1371/journal.pgen.1000801

DO - 10.1371/journal.pgen.1000801

M3 - Article

C2 - 20062519

SN - 1553-7390

VL - 6

SP - -

JO - PLoS Genetics

JF - PLoS Genetics

IS - 1

M1 - e1000801

ER -