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RTEL1 Is a Replisome-Associated Helicase That Promotes Telomere and Genome-Wide Replication

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Science  11 Oct 2013:
Vol. 342, Issue 6155, pp. 239-242
DOI: 10.1126/science.1241779

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RTEL1 in DNA Replication

Genome stability requires the coordinate action of a variety of DNA maintenance systems. The DNA helicase, RTEL1 (regulator of telomere length 1), disassembles recombination intermediates to avoid dangerous by-products. RTEL1 also limits excessive meiotic crossing over and disassembles telomere T loops. Vannier et al. (p. 239) now show that mammalian RTEL1 is part of the DNA replication machinery. RTEL1 binds to proliferating cell nuclear antigen (PCNA), an interaction that was important for normal DNA replication, replication fork stability, and telomere stability. The RTEL1-PCNA interaction was also critical for protecting cells against tumorigenesis but was not required for telomere T-loop disassembly.

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.

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