TRF2 Recruits RTEL1 to Telomeres in S Phase to Promote T-Loop Unwinding

Summary

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.

Graphical Abstract

Highlights

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  An S phase-specific TRF2-RTEL1 interaction is required for t-loop disassembly

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  RTEL1 C4C4 and PIP-box motifs control distinct genome maintenance pathways

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  A unique binding site in TRF2 interacts with and recruits RTEL1 to telomeres

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  TRF2-RTEL1 interaction is abolished by the disease causing RTEL1 ^R1264H mutation

Abstract

RTEL1 is an essential DNA helicase that disassembles telomere loops (t-loops) to maintain integrity of chromosome ends. Sarek et al. now establish the mechanism by which RTEL1 is recruited to telomeres to execute t-loop unwinding, which is dependent on an S phase-specific interaction between RTEL1 and the shelterin component TRF2.