日本国家癌症中心研究所Kenkichi Masutomi研究组发现，磷酸化hTERT对R环结构的维护可保持基因组完整性。相关论文于2024年5月28日在线发表在《自然—细胞生物学》杂志上。

研究人员报告了人类端粒酶反转录酶（hTERT）的RNA依赖性RNA聚合酶（RdRP）活性调控RNA-DNA 杂交（R-环）的形成。研究人员发现，磷酸化形式的hTERT（p-hTERT）在端粒酶阳性细胞，和具有端粒替代性延长（ALT）活性的端粒酶阴性细胞的核斑点中，都表现出RdRP活性。p-hTERT不与核斑点中的端粒酶RNA成分结合，而是与TERRA RNA结合以解决R环问题。在ALT细胞中靶向TERT基因可消减RdRP活性，并抑制肿瘤生长。

通过基因组规模的CRISPR功能缺失筛选，研究人员发现范可尼贫血症/BRCA 基因是hTERT RdRP的合成致死伙伴。RdRP和范可尼贫血症/BRCA基因失活会导致R环结构积累和DNA损伤。这些发现表明，p-hTERT的RdRP活性通过去除R环结构来防止基因组的不稳定性。

据悉，由于R-环的异常积累会导致DNA损伤和基因组不稳定，因此细胞会表达R-环结构的调节因子。

附：英文原文

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

Author: 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

Issue&Volume: 2024-05-28

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.

DOI: 10.1038/s41556-024-01427-6

Source: https://www.nature.com/articles/s41556-024-01427-6