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通过化hTERT维护R环结构,从而保持基因组完整性

Mitsuhiro Machitani¹, Akira Nomura^1,2, Taro Yamashita³

¹Division of Cancer Stem Cell, National Cancer Center Research Institute, Tokyo, Japan.

Nature cell biology

|May 28, 2024

概括

酸化人类端粒酶 (hTERT) 具有依赖于RNA的RNA聚合酶 (RdRP) 活性,可以分解RNA-DNA杂交物 (R-循环),防止基因组的不稳定. 向hTERT RdRP活动会损害瘤生长,并揭示与Fanconi贫血症/BRCA基因的合成致命相互作用.

科学领域:

分子生物学分子生物学
遗传学遗传学是一个
癌症研究癌症研究

背景情况:

异常的RNA-DNA混合体 (R-循环) 与DNA损伤和基因组不稳定性有关.
细胞调节器对于管理R循环结构至关重要.
了解R循环调节是防止基因组不稳定性的关键.

研究的目的:

研究人类端粒酶逆转录酶 (hTERT) 在调节R循环形成中的作用.
为了确定hTERT的新型调节剂和功能,超出端粒维护.
探索针对癌症R环平衡的治疗策略.

主要方法:

使用RNA依赖RNA聚合酶 (RdRP) 试验来表征hTERT活动.
采用免疫光和共免疫沉来研究蛋白质定位和相互作用.
进行了基因组规模的CRISPR功能丧失屏幕,以识别合成致命相互作用.
在替代延长端粒 (ALT) 细胞中的向TERT基因表达.

主要成果:

酸化hTERT (p-hTERT) 在核斑点中表现出RdRP活性.
p-hTERT与TERRA RNAs结合,以解决R循环,独立于端粒酶RNA.
在ALT细胞中准TERT基因降低了RdRP活性,并影响了瘤生长.
芬科尼贫血/BRCA基因被确定为hTERT RdRP.的合成致命合作伙伴.
对hTERT RdRP和Fanconi贫血/BRCA基因的失活导致R循环积累和DNA损伤.

结论:

p-hTERT的RdRP活性在解决R循环和保持基因组稳定性方面发挥着关键作用.
hTERT的功能超出了端粒维护范围,可以积极调节R循环结构.
向hTERT RdRP活动为癌症提供了潜在的治疗途径,特别是与向DNA修复途径的疗法相结合,如Fanconi贫血/BRCA.

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