Maintenance of R-loop structures by phosphorylated hTERT preserves genome integrity.

Autor: Machitani M; Division of Cancer Stem Cell, National Cancer Center Research Institute, Tokyo, Japan., Nomura A; Division of Cancer Stem Cell, National Cancer Center Research Institute, Tokyo, Japan.; Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Isehara, Japan., Yamashita T; Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan., Yasukawa M; Division of Cancer Stem Cell, National Cancer Center Research Institute, Tokyo, Japan., Ueki S; Division of Cancer Stem Cell, National Cancer Center Research Institute, Tokyo, Japan., Fujita KI; Division of Cancer Stem Cell, National Cancer Center Research Institute, Tokyo, Japan., Ueno T; Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan., Yamashita A; Department of Investigative Medicine, University of the Ryukyus Graduate School of Medicine, Nakagami, Japan., Tanzawa Y; Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Isehara, Japan., Watanabe M; Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Isehara, Japan., Taniguchi T; Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Japan., Saitoh N; Division of Cancer Biology, The Cancer Institute of JFCR, Tokyo, Japan., Kaneko S; Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan., Kato Y; Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan.; Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan., Mano H; Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan., Masutomi K; Division of Cancer Stem Cell, National Cancer Center Research Institute, Tokyo, Japan. kmasutom@ncc.go.jp.
Jazyk: angličtina
Zdroj: Nature cell biology [Nat Cell Biol] 2024 Jun; Vol. 26 (6), pp. 932-945. Date of Electronic Publication: 2024 May 28.
DOI: 10.1038/s41556-024-01427-6
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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