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.
Highlights
Werner syndrome (WS) is associated with rapid acceleration of aging, and is caused by mutations in the RecQ family DNA helicase gene, WRN [1]
The protein linked to Werner syndrome, WRN, has both helicase and exonuclease activities and is thought to be involved in DNA repair, including the resolution of replication fork arrest as well as in telomere maintenance
We take advantage of the Caenorhabditis elegans germ cell system to explore DNA damage response defects associated with WRN, and we focus on the role of wrn in the cell cycle checkpoint in response to DNA replication blockage and ionizing radiation (IR)
Summary
Werner syndrome (WS) is associated with rapid acceleration of aging, and is caused by mutations in the RecQ family DNA helicase gene, WRN [1]. The role of WRN in premature aging may be linked to telomere regulation. A link between WRN, telomere DNA metabolism and progeria has been demonstrated in mouse Wrn and Terc (telomerase RNA) knockout models [7]. Symptoms of Werner syndrome appeared in late-generation Wrn and Terc double mutant mice together with accelerated telomere loss, while the corresponding single mutants did not show such phenotypes. The role of WRN in telomere DNA metabolism is supported by a report showing that WRN localizes to telomeric DNA during the S-phase of telomerase-defective ALT cells and by its ability to resolve telomeric D loops via its helicase and nuclease functions in vitro [8]
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