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

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. © 2010 lee et al.