TY - JOUR
T1 - The DNA Damage Machinery and Homologous Recombination Pathway Act Consecutively to Protect Human Telomeres
AU - Verdun, Ramiro E.
AU - Karlseder, Jan
N1 - Funding Information:
We thank V. Lundblad, A. Dillin, and the Karlseder Laboratory for critical comments and Titia de Lange for TIN2 antibodies and for pSxNEO 540 T 2 AG 3 . This work was supported by the NIH (RO1 GM06525 to J.K.). J.K. is a Hearst Endowment Assistant Professor, and R.E.V. is a Leukemia and Lymphoma Society fellow.
PY - 2006/11/17
Y1 - 2006/11/17
N2 - Telomeres protect chromosome ends from being detected as lesions and from triggering DNA damage checkpoints. Paradoxically, telomere function depends on checkpoint proteins such as ATM and ATR, but a molecular model explaining this seemingly contradictory relationship has been missing so far. Here we show that the DNA damage machinery acts on telomeres in at least two independent steps. First, the ATR-dependent machinery is recruited to telomeres before telomere replication is completed, likely in response to single-stranded DNA resulting from replication fork stalling. Second, after replication, telomeres attract ATM and the homologous recombination (HR) machinery. In vivo and in vitro results suggest that the HR machinery is required for formation of a telomere-specific structure at chromosome ends after replication. Our results suggest that telomere ends need to be recognized as DNA damage to complete end replication and to acquire a structure that is essential for function.
AB - Telomeres protect chromosome ends from being detected as lesions and from triggering DNA damage checkpoints. Paradoxically, telomere function depends on checkpoint proteins such as ATM and ATR, but a molecular model explaining this seemingly contradictory relationship has been missing so far. Here we show that the DNA damage machinery acts on telomeres in at least two independent steps. First, the ATR-dependent machinery is recruited to telomeres before telomere replication is completed, likely in response to single-stranded DNA resulting from replication fork stalling. Second, after replication, telomeres attract ATM and the homologous recombination (HR) machinery. In vivo and in vitro results suggest that the HR machinery is required for formation of a telomere-specific structure at chromosome ends after replication. Our results suggest that telomere ends need to be recognized as DNA damage to complete end replication and to acquire a structure that is essential for function.
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U2 - 10.1016/j.cell.2006.09.034
DO - 10.1016/j.cell.2006.09.034
M3 - Article
C2 - 17110331
AN - SCOPUS:33750801681
VL - 127
SP - 709
EP - 720
JO - Cell
JF - Cell
SN - 0092-8674
IS - 4
ER -