The Mre11 Complex and the Response to Dysfunctional Telomeres

Abstract

ABSTRACTIn this study, we examine the telomeric functions of the mammalian Mre11 complex by using hypomorphicMre11andNbs1mutants (Mre11ATLD1/ATLD1andNbs1ΔB/ΔB, respectively). No telomere shortening was observed inMre11ATLD1/ATLD1cells after extensive passage through culture, and the rate of telomere shortening in telomerase-deficient (TertΔ/Δ)Mre11ATLD1/ATLD1cells was the same as that inTertΔ/Δalone. Although telomeres from late-passageMre11ATLD1/ATLD1TertΔ/Δcells were as short as those fromTertΔ/Δ, the incidence of telomere fusions was reduced. This effect on fusions was also evident upon acute telomere dysfunction inMre11ATLD1/ATLD1andNbs1ΔB/ΔBcells rendered Trf2 deficient bycre-mediatedTRF2inactivation than in wild-type cells. The residual fusions formed in Mre11 complex mutant cells exhibited a strong tendency toward chromatid fusions, with an almost complete bias for fusion of telomeres replicated by the leading strand. Finally, the response to acute telomere dysfunction was strongly impaired by Mre11 complex hypomorphism, as the formation of telomere dysfunction-induced DNA damage foci was reduced in bothcre-infectedMre11ATLD1/ATLD1Trf2F/ΔandNbs1ΔB/ΔBTrf2F/Fcells. These data indicate that the Mre11 complex influences the cellular response to telomere dysfunction, reminiscent of its influence on the response to interstitial DNA breaks, and suggest that it may promote telomeric DNA end processing during DNA replication.