Premium
NHP2 downregulation counteracts h TR ‐mediated activation of the DNA damage response at ALT telomeres
Author(s) -
Raghunandan Maya,
Geelen Dan,
Majerova Eva,
Decottignies Anabelle
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020106336
Subject(s) - biology , telomere , downregulation and upregulation , dna damage , dna , microbiology and biotechnology , genetics , gene
About 10% of cancer cells employ the “alternative lengthening of telomeres” (ALT) pathway instead of re‐activating the h TERT subunit of human telomerase. The h TR RNA subunit is also abnormally silenced in some ALT + cells not expressing h TERT , suggesting a possible negative non‐canonical impact of h TR on ALT. Indeed, we show that ectopically expressed h TR reduces phosphorylation of ssDNA‐binding protein RPA (p‐RPA S33 ) 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 naturally retain h TR expression, NHP2 H/ACA ribonucleoprotein levels are downregulated, likely in order to restrain DNA damage response (DDR) activation at telomeres through reduced 53BP1 recruitment. This unexpected role of NHP2 is independent from h TR ’s non‐canonical function in modulating telomeric p‐RPA S33 . Collectively, our study shines new light on the interference between telomerase‐ and ALT‐dependent pathways and unravels a crucial role for h TR and NHP2 in DDR regulation at ALT telomeres.