Homologous recombination generates T-loop-sized deletions at human telomeres.
The t-loop structure of mammalian telomeres is thought to repress nonhomologous end joining (NHEJ) at natural chromosome ends. Telomere NHEJ occurs upon loss of TRF2, a telomeric protein implicated in t-loop formation. Here we describe a mutant allele of TRF2, TRF2DeltaB, that suppressed NHEJ but induced catastrophic deletions of telomeric DNA. The deletion events were stochastic and occurred rapidly, generating dramatically shortened telomeres that were accompanied by a DNA damage response and induction of senescence. TRF2DeltaB-induced deletions depended on XRCC3, a protein implicated in Holliday junction resolution, and created t-loop-sized telomeric circles. These telomeric circles were also detected in unperturbed cells and suggested that t-loop deletion by homologous recombination (HR) might contribute to telomere attrition. Human ALT cells had abundant telomeric circles, pointing to frequent t-loop HR events that could promote rolling circle replication of telomeres in the absence of telomerase. These findings show that t-loop deletion by HR influences the integrity and dynamics of mammalian telomeres.
Wang
Richard C
RC
Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Smogorzewska
Agata
A
de Lange
Titia
T
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D004261:DNA Replication / Q000502:physiology; D004270:DNA, Circular / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D011995:Recombination, Genetic / Q000502:physiology*; D004718:Saccharomycetales / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D004270:DNA, Circular; D004268:DNA-Binding Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D035341:Telomeric Repeat Binding Protein 2; C110901:X-ray repair cross complementing protein 3