The DNA Helicase RTEL1 Is Essential for Telomere Replication

Regulator of telomere elongation helicase 1 (RTEL1) is a DNA helicase that ensures telomere stability via removal of telomeric T loops and G-quadruplex (G4) DNA secondary structures that impede efficient telomere replication. In addition, RTEL1 has been implicated in a cancer predisposition syndrome and as a susceptibility locus in glioma, suggesting that it may act as a tumor suppressor. However, the mechanisms by which RTEL1 regulates telomere integrity and the role of this function in tumor suppression remain unclear. Vannier and colleagues found that RTEL1 interacted with the replisome at replication foci via direct binding to proliferating cell nuclear antigen (PCNA), a processivity factor for DNA polymerase. Mutation of the C-terminal PIP box interaction motif in RTEL1 impaired its interaction with PCNA and triggered senescence and cell-cycle arrest in late S–G₂phase, suggesting a role for RTEL1 in genome-wide DNA replication. Indeed, disruption of the RTEL1–PCNA interaction globally decreased DNA replication fork extension and increased replication fork asymmetry and origin firing, suggesting that the RTEL1–PCNA complex prevents replication fork stalling and collapse. Moreover, although interaction of RTEL1 with PCNA was not essential for disassembly of telomeric T-loop structures during S-phase, RTEL1 binding to PCNA was required to suppress telomere fragility in metaphase. This effect was mediated by RTEL1-dependent unwinding of telomeric G4-DNA structures, which has been shown to facilitate telomere replication. Furthermore, mice expressing PIP box-mutant RTEL1 exhibited accelerated tumor formation, increased predisposition to medulloblastoma, and decreased survival; this phenotype was associated with accumulation of chromosomal fusions and fragile telomeres, suggesting that the interaction of RTEL1 with PCNA protects cells from genomic instability. These results establish a critical role for RTEL1-mediated regulation of telomere and genome replication in the maintenance of telomere integrity and suppression of tumorigenesis.

Vannier JB, Sandhu S, Petalcorin MI, Wu X, Nabi Z, Ding H, et al. RTEL1 is a replisome-associated helicase that promotes telomere and genome-wide replication. Science 2013;342:239–42.