Homologous recombination generates t-loop-sized deletions at human telomeres

Richard C. Wang, Agata Smogorzewska, Titia De Lange

Research output: Contribution to journalArticle

400 Scopus citations

Abstract

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, TRF2ΔB, 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. TRF2ΔB-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.

Original languageEnglish (US)
Pages (from-to)355-368
Number of pages14
JournalCell
Volume119
Issue number3
DOIs
StatePublished - Oct 29 2004

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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