The terminal telomeric DNA sequence determines the mechanism of dysfunctional telomere fusion.
Mammalian telomeres consist of tandem DNA repeats that bind protective protein factors collectively termed shelterins. Telomere disruption typically results in genome instability induced by telomere fusions. The mechanism of telomere fusion varies depending on the means of telomere disruption. Here, we investigate telomere fusions caused by overexpression of mutant telomerases that add mutated telomeric repeats, thereby compromising shelterin binding to telomeric termini. While all mutant telomeric sequences tested induced heterodicentric chromosome fusions in ATM-competent cells, only those mutant repeat sequences with significant self complementarity induced ATM-independent sister chromatid and isodicentric chromosome fusions. Thus, once a telomere becomes dysfunctional, the terminal telomeric sequence itself determines the fate of that telomere. These results suggest that annealing of self-complementary DNA sequence engages an alternative telomere fusion pathway in human cells, and provide one explanation for the conspicuous lack of self complementarity in the majority of known naturally occurring eukaryotic telomeric sequences.
Stohr
Bradley A
BA
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
Xu
Lifeng
L
Blackburn
Elizabeth H
EH
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002842:Chromatids / Q000235:genetics / Q000378:metabolism*; D002877:Chromosomes, Human / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D020080:Tandem Repeat Sequences; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D019098:Telomerase