title: RTEL1 is a replisome-associated helicase that promotes telomere and genome-wide replication.
abstract: 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.
authors.affiliation: DNA Damage Response Laboratory, London Research Institute, Cancer Research UK, Clare Hall, South Mimms, UK.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Vannier
authors.forename: Sumit
authors.initials: S
authors.lastname: Sandhu
authors.forename: Mark I R
authors.initials: MI
authors.lastname: Petalcorin
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wu
authors.forename: Zinnatun
authors.initials: Z
authors.lastname: Nabi
authors.forename: Hao
authors.initials: H
authors.lastname: Ding
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Boulton
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D016678:Genome / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D016615:Telomere / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; C527736:regulator of telomere length protein, mouse; D004265:DNA Helicases