TY - JOUR
T1 - Homologous recombination generates t-loop-sized deletions at human telomeres
AU - Wang, Richard C.
AU - Smogorzewska, Agata
AU - De Lange, Titia
N1 - Funding Information:
We are grateful to Kiyoshi Miyagawa, Michael Liskay, John Petrini, Thanos Halazonetis, Paul Hasty, Lexicon Genetics, Fred Alt, Margeret Zdzienicka, Thomas Kunkel, Alan Clark, Winfried Edelman, Hein te Riele, Phillip Smiraldo, and Douglas Pittman for generous gifts of reagents and cell lines. We thank Xu-Dong Zhu, Giulia Celli, Jan Karlseder, Hiro Takai, Diego Loayza, Dirk Hockemeyer, Susan Bailey, and Maria Blasco for invaluable assistance with protocols. Jim Haber and members of the de Lange lab are thanked for helpful discussions and comments on the paper. This work was supported by a grant to T.d.L. from the NIH (GM49046). R.C.W. and A.S. were supported by an NIH MSTP grant (GM07739) to the Cornell/RU/MSK Tri-Institutional MD/PhD program.
PY - 2004/10/29
Y1 - 2004/10/29
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2004.10.011
DO - 10.1016/j.cell.2004.10.011
M3 - Article
C2 - 15507207
AN - SCOPUS:7044232011
SN - 0092-8674
VL - 119
SP - 355
EP - 368
JO - Cell
JF - Cell
IS - 3
ER -