期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2208669119
关键词
alternative lengthening of telomeres; telomere transcription; TERRA; Mus81
资金
- Fundacao para a Ciencia e a Tecnologia [PTDC/BIA-MOL/6624/2020, PTDC/MED-ONC/7864/2020, 2021.00143.CEECIND]
- European Molecular Biology Organization [IG3576]
- LaCaixa Foundation [LCF/PR/HP21/52310016]
This study demonstrates that telomere transcription is a major trigger of alternative lengthening of telomeres (ALT) activity. Inhibiting the transcription of telomeric long noncoding RNA TERRA can suppress ALT features. Additionally, experimentally increasing TERRA transcription leads to rapid loss of telomeric DNA.
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.
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