期刊
CELL
卷 172, 期 3, 页码 439-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2017.11.047
关键词
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资金
- EMBO long-term fellowship [ALTF 439-2015, ALTF 156-2013]
- European Union's Horizon research and innovation program under the Marie Sklodowska-Curie [702430]
- Francis Crick Institute - Cancer Research UK [FC0010048]
- UK Medical Research Council [FC0010048]
- Wellcome Trust [FC0010048]
- European Research Council (ERC) Advanced Investigator Grant (TelMetab) [742437]
- Wellcome Trust Senior Investigator Grant
- Cancer Research UK [11581] Funding Source: researchfish
- The Francis Crick Institute [10627, 703228 - RTEL1, 742437-TelMetab] Funding Source: researchfish
- The Francis Crick Institute
- Cancer Research UK [10048] Funding Source: researchfish
- Marie Curie Actions (MSCA) [702430] Funding Source: Marie Curie Actions (MSCA)
- European Research Council (ERC) [742437] Funding Source: European Research Council (ERC)
Telomere maintenance critically depends on the distinct activities of telomerase, which adds telomeric repeats to solve the end replication problem, and RTEL1, which dismantles DNA secondary structures at telomeres to facilitate replisome progression. Here, we establish that reversed replication forks are a pathological substrate for telomerase and the source of telomere catastrophe in Rtel1(-/-) cells. Inhibiting telomerase recruitment to telomeres, but not its activity, or blocking replication fork reversal through PARP1 inhibition or depleting UBC13 or ZRANB3 prevents the rapid accumulation of dysfunctional telomeres in RTEL1-deficient cells. In this context, we establish that telomerase binding to reversed replication forks inhibits telomere replication, which can be mimicked by preventing replication fork restart through depletion of RECQ1 or PARG. Our results lead us to propose that telomerase inappropriately binds to and inhibits restart of reversed replication forks within telomeres, which compromises replication and leads to critically short telomeres.
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