Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis

Abstract

SUMMARYGenome sequencing studies have revealed a number of cancer-associated mutations in the telomerebinding factor POT1. Here, we show that when combined with p53 deficiency, depletion of murine POT1a in common lymphoid progenitor cells fosters genetic instability, accelerates the onset, and increases the severity of T cell lymphomas. In parallel, we examined human and mouse cells carrying POT1 mutations found in cutaneous T cell lymphoma (CTCL) patients. Inhibition of POT1 activates ATRdependent DNA damage signaling and induces telomere fragility, replication fork stalling, and telomere elongation. Our data suggest that these phenotypes are linked to impaired CST (CTC1-STN1-TEN1) function at telomeres. Lastly, we show that proliferation of cancer cells lacking POT1 is enabled by the attenuation of the ATR kinase pathway. These results uncover a role for defective telomere replication during tumorigenesis.

DNA Replication Controls Volume 2

“…However, the hpr1-101 allele, which contains a point mutation in the hpr1 gene, fails to cause hyperrecombination phenotypes although transcriptional elongation and mRNA export are inhibited in the mutant. This loss of the hyperrecombination phenotype is correlated with the absence of replication fork blockage in hpr1 mutants, suggesting that hyperrecombination is caused by stalled replication forks [212]. Although the molecular mechanisms involved in replication pausing at transcription sites still remain unclear, DNA polymerase ε, a major replicative enzyme, is enriched throughout open reading frames in S. cerevisiae.…”

“…The function of POT1 in efficient replication seems to be mediated by the interaction with the CST (CTC1-STN1-TEN1) ternary complex [212], which stimulates replication fork restart. Knockdown of CTC1 or STN1 induces fragile telomere and TIFs and is epistatic to POT1 mutations [212]. Another function of POT1 is the unwinding of G4 DNA on the G-rich template strands [121][122][123][124].…”

“…In fission yeast, replication fork pausing was also linked to increased recombination at the leu2 locus, which is transcribed by RNA Pol II [193]. Further investigation suggests that stalled replication is a prerequisite to hyper-recombination [212]. Null mutants of S. cerevisiae Hpr1, a component of the THO complex, exhibit hyperrecombination phenotypes in addition to defects in transcriptional elongation and mRNA export to the cytoplasm [213][214][215][216][217][218].…”

“…Because replication forks stall naturally at mammalian telomeres, an ATR-dependent fork restart mechanism is needed to complete DNA replication [227][228][229]. Knockdown of expression of CST components decreases bromodeoxyuridine incorporation at telomeres after release from hydroxyurea-induced replication fork arrest, and elicits telomere fragility [212,226,[230][231][232][233][234][235][236]. Several lines of evidence suggest that CST contributes to fork restart not only in telomeres but also genome-wide under conditions of replication stress [232,233,235,237].…”

“…TRF1 acts as a platform to recruit POT1 through the interaction mediated by TIN2-TPP1 in shelterin [56,205]. Mutations encoding POT1 variants defective in ssDNA binding have been found in patients with cancer, and expression of these variants elicits fragile telomere and ATR-dependent TIFs, which are signs of telomeric replication defects [209][210][211][212]. The function of POT1 in efficient replication seems to be mediated by the interaction with the CST (CTC1-STN1-TEN1) ternary complex [212], which stimulates replication fork restart.…”