Journal
SCIENCE
Volume 342, Issue 6155, Pages 239-242Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1241779
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Funding
- Cancer Research UK
- European Research Council (ERC)
- Royal Society Wolfson Research Merit Award
- Canada Research Chair program
- Canada Institute of Health Research
- Manitoba Institute of Child Health
- Terry Fox Research Institute
- ERC
- Natural Sciences and Engineering Research Council of Canada
- Manitoba Health Research Council
- Cancer Research UK [11581] Funding Source: researchfish
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Regulator of telomere length 1 (RTEL1) is an essential DNA helicase that disassembles telomere loops (T loops) and suppresses telomere fragility to maintain the integrity of chromosome ends. We established that RTEL1 also associates with the replisome through binding to proliferating cell nuclear antigen (PCNA). Mouse cells disrupted for the RTEL1-PCNA interaction (PIP mutant) exhibited accelerated senescence, replication fork instability, reduced replication fork extension rates, and increased origin usage. Although T-loop disassembly at telomeres was unaffected in the mutant cells, telomere replication was compromised, leading to fragile sites at telomeres. RTEL1-PIP mutant mice were viable, but loss of the RTEL1-PCNA interaction accelerated the onset of tumorigenesis in p53-deficient mice. We propose that RTEL1 plays a critical role in both telomere and genome-wide replication, which is crucial for genetic stability and tumor avoidance.
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