Abstract

Regulator of telomere length 1 (RTEL1) is an essential Fe-S dependent DNA helicase that regulates homologous recombination, disassembles telomere (T)-loops and suppresses telomere fragility to maintain the integrity of the genome. The emergence of RTEL1 variants that confer increased susceptibility to high-grade Glioma, Astrocytomas and Glioblastomas has highlighted the importance of RTEL1 in human cancers. Mutations in RTEL1 have also been implicated in Hoyerall-Hreidarsson syndrome (HHS), a severe form of the bone marrow failure and cancer predisposition disorder, Dyskeratosis Congenita. We previously reported that RTEL1 binds to the replisome via a PIP -box dependent interaction with PCNA . Disruption of the RTEL1 -PCNA interaction in mice compromised genome-wide and telomere replication, and accelerated the onset of tumourigenesis in p53 deficient animals. Unexpectedly, the RTEL1 -PCNA interaction was found to be dispensable for T-loop disassembly, which suggested the existence of a distinct mechanism for recruiting RTEL1 to telomeres. Indeed, we have discovered that RTEL1 is recruited to telomeres via an S-phase specific interaction with the shelterin component TRF2 . We proceeded to identify a single point mutation within TRF2 that abrogates the interaction with RTEL1 and phenocopies the Rtel1 null phenotype. Finally, we demonstrated that the RTEL1 -TRF2 interaction is compromised by the R1264H mutation in RTEL1 , which is causal for HHS and exists at a carrier frequency of 1 in 100 within the Ashkenazi Jew population. These results define a clinically important interaction between RTEL1 and TRF2 , which is critical for the timely disassembly of T-loops during S-phase of the cell cycle.

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