Silva, BrunoArora, RajikaAzzalin, Claus Maria2022-09-212022-09-212022Proc Natl Acad Sci USA. 2022 Sep 27;119(39):e22086691190027-8424http://hdl.handle.net/10451/54541Copyright © 2022 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).A substantial number of human cancers are telomerase-negative and elongate physiologically damaged telomeres through a break-induced replication (BIR)-based mechanism known as alternative lengthening of telomeres (ALT). We recently demonstrated that inhibiting the transcription of the telomeric long noncoding RNA TERRA suppresses telomere damage and ALT features, indicating that telomere transcription is a main trigger of ALT activity. Here we show that experimentally increased TERRA transcription not only increases ALT features, as expected, but also causes rapid loss of telomeric DNA through a pathway that requires the endonuclease Mus81. Our data indicate that the ALT mechanism can endanger telomere integrity if not properly controlled and point to TERRA transcription as a uniquely versatile target for therapy.engMus81TERRAAlternative lengthening of telomeresTelomere transcriptionjournal article10.1073/pnas.22086691191091-6490