hTR and NHP2 independently activate the DNA damage response at ALT telomeres
(2021) The EMBO journal — Vol. 15, n° 40(6), p. e106336 (2021)
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- Authors
Raghunandan, Maya 
- Abstract
- About 10% of cancer cells employ the Alternative Lengthening of Telomeres (ALT) pathway instead of re-activating the hTERT subunit of telomerase. The hTR RNA subunit is also abnormally silenced in some ALT+ cells not expressing hTERT, suggesting a possible negative impact of hTR on ALT, independently of telomerase. Accordingly, ectopically-expressed hTR reduces p-RPAS33 levels at ALT telomeres by promoting the hnRNPA1- and DNA-PK-dependent depletion of telomere-bound RPA. The resulting defective ATR signaling at telomeres impairs the recruitment of homologous recombination protein, RAD51. This induces ALT telomere fragility, increases POLD3-dependent C-circle production and promotes the recruitment of 53BP1 DNA damage marker at telomeres. In ALT+ cells that naturally retain hTR expression, NHP2 H/ACA ribonucleoprotein levels are downregulated, likely to restrain DNA damage response (DDR) activation at telomeres through a reduced recruitment of 53BP1. This unexpected role of NHP2 is independent from hTR’s non-canonical function in modulating telomeric p-RPAS33. Collectively, our study shines new light on the interference between telomerase- and ALT-pathways and unravels a crucial role for hTR and NHP2 in regulating DDR at ALT telomeres.
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Citations
Raghunandan, M., Geelen, D., Majerova, E., & Decottignies, A. (2021). hTR and NHP2 independently activate the DNA damage response at ALT telomeres. The EMBO journal, 15(40(6)), e106336. https://doi.org/10.15252/embj.2020106336 (Original work published 2021)