Publication

Nature Cell Biology 26, 6, 932-945 (2024)
Maintenance of R-loop structures by phosphorylated hTERT preserves genome integrity

Author

Machitani M, Nomura A, Yamashita T, Yasukawa M, Ueki S, Fujita KI, Ueno T, Yamashita A, Tanzawa Y, Watanabe M, Taniguchi T, Saitoh N, Kaneko S, Kato Y, Mano H, Masutomi K.

Category

Paper

Abstract

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.
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