دورية أكاديمية
Maintenance of R-loop structures by phosphorylated hTERT preserves genome integrity.
| العنوان: | Maintenance of R-loop structures by phosphorylated hTERT preserves genome integrity. |
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| المؤلفون: | Machitani, Mitsuhiro, Nomura, Akira, Yamashita, Taro, Yasukawa, Mami, Ueki, Saori, Fujita, Ken-Ichi, Ueno, Toshihide, Yamashita, Akio, Tanzawa, Yoshikazu, Watanabe, Masahiko, Taniguchi, Toshiyasu, Saitoh, Noriko, Kaneko, Shuichi, Kato, Yukinari, Mano, Hiroyuki, Masutomi, Kenkichi |
| المصدر: | Nat Cell Biol ; ISSN:1476-4679 ; Volume:26 ; Issue:6 |
| بيانات النشر: | Nature Publishing Group |
| سنة النشر: | 2024 |
| المجموعة: | PubMed Central (PMC) |
| الوصف: | As aberrant accumulation of RNA-DNA hybrids (R-loops) causes DNA damage and genome instability, cells express regulators of R-loop structures. Here we report that RNA-dependent RNA polymerase (RdRP) activity of human telomerase reverse transcriptase (hTERT) regulates R-loop formation. We found that the phosphorylated form of hTERT (p-hTERT) exhibits RdRP activity in nuclear speckles both in telomerase-positive cells and telomerase-negative cells with alternative lengthening of telomeres (ALT) activity. The p-hTERT did not associate with telomerase RNA component in nuclear speckles but, instead, with TERRA RNAs to resolve R-loops. Targeting of the TERT gene in ALT cells ablated RdRP activity and impaired tumour growth. Using a genome-scale CRISPR loss-of-function screen, we identified Fanconi anaemia/BRCA genes as synthetic lethal partners of hTERT RdRP. Inactivation of RdRP and Fanconi anaemia/BRCA genes caused accumulation of R-loop structures and DNA damage. These findings indicate that RdRP activity of p-hTERT guards against genome instability by removing R-loop structures. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://doi.org/10.1038/s41556-024-01427-6Test; https://pubmed.ncbi.nlm.nih.gov/38806647Test |
| DOI: | 10.1038/s41556-024-01427-6 |
| الإتاحة: | https://doi.org/10.1038/s41556-024-01427-6Test https://pubmed.ncbi.nlm.nih.gov/38806647Test |
| حقوق: | © 2024. The Author(s), under exclusive licence to Springer Nature Limited. |
| رقم الانضمام: | edsbas.CBCCD524 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41556-024-01427-6 |
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