title: TRF2 recruits RTEL1 to telomeres in S phase to promote t-loop unwinding.
abstract: The helicase RTEL1 promotes t-loop unwinding and suppresses telomere fragility to maintain the integrity of vertebrate telomeres. An interaction between RTEL1 and PCNA is important to prevent telomere fragility, but how RTEL1 engages with the telomere to promote t-loop unwinding is unclear. Here, we establish that the shelterin protein TRF2 recruits RTEL1 to telomeres in S phase, which is required to prevent catastrophic t-loop processing by structure-specific nucleases. We show that the TRF2-RTEL1 interaction is mediated by a metal-coordinating C4C4 motif in RTEL1, which is compromised by the Hoyeraal-Hreidarsson syndrome (HHS) mutation, RTEL1(R1264H). Conversely, we define a TRF2(I124D) substitution mutation within the TRFH domain of TRF2, which eliminates RTEL1 binding and phenocopies the RTEL1(R1264H) mutation, giving rise to aberrant t-loop excision, telomere length heterogeneity, and loss of the telomere as a circle. These results implicate TRF2 in the recruitment of RTEL1 to facilitate t-loop disassembly at telomeres in S phase.
authors.affiliation: Clare Hall Laboratories, London Research Institute, Cancer Research UK, Clare Hall, South Mimms, Hertfordshire EN6 3LD, UK.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Sarek
authors.affiliation: Clare Hall Laboratories, London Research Institute, Cancer Research UK, Clare Hall, South Mimms, Hertfordshire EN6 3LD, UK.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Vannier
authors.affiliation: Clare Hall Laboratories, London Research Institute, Cancer Research UK, Clare Hall, South Mimms, Hertfordshire EN6 3LD, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Panier
authors.affiliation: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: John H J
authors.initials: JHJ
authors.lastname: Petrini
authors.affiliation: Clare Hall Laboratories, London Research Institute, Cancer Research UK, Clare Hall, South Mimms, Hertfordshire EN6 3LD, UK. Electronic address: simon.boulton@cancer.org.uk.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Boulton
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004265:DNA Helicases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008677:Metaphase; D051379:Mice; D008957:Models, Genetic; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D016196:S Phase; D016615:Telomere / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism / Q000502:physiology*
chemical_list: C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; C532890:RTEL1 protein, human; D004265:DNA Helicases