NHP2 downregulation counteracts hTR-mediated activation of the DNA damage response at ALT telomeres

ABSTRACT: About 10% of cancer cells employ the 'Alternative Lengthening of Telomeres' (ALT) pathway instead of re-activating the hTERT subunit of human telomerase. The hTR RNA subunit is also abnormally silenced in some ALT+ cells not expressing hTERT, suggesting a possible negative non-canonical impact of hTR on ALT. Indeed, we show that ectopically-expressed hTR reduces phosphorylation of ssDNA-binding protein RPA (p-RPAS33) at ALT telomeres by promoting the hnRNPA1- and DNA-PK-dependent depletion of RPA. The resulting defective ATR checkpoint signaling at telomeres impairs recruitment of the homologous recombination protein, RAD51. This induces ALT telomere fragility, increases POLD3-dependent C-circle production, and promotes the recruitment of the DNA damage marker 53BP1. In ALT+ cells that nat

SUBMITTER: Dr. Maya Raghunandan 

PROVIDER: S-SCDT-EMBOJ-2020-106336 | biostudies-other |

REPOSITORIES: biostudies-other