美国波士顿儿童医院Suneet Agarwal团队发现，胸苷核苷酸代谢调控人类端粒的长度。相关论文于2023年3月23日在线发表在《自然—遗传学》杂志上。
研究人员进行了全基因组的CRISPR-Cas9功能性端粒长度筛选，并确定胸苷（dT）核苷酸的代谢是人类端粒维持的一个限制因素。使用CRISPR-Cas9进行的靶向遗传破坏揭示了dT核苷酸代谢途径中的多个端粒长度控制点：通过删除编码核胸苷激酶（TK1）的基因减少dT核苷酸的回收，或通过敲除胸苷酸合成酶基因（TYMS）从头生产，能够减少端粒长度，而失活脱氧核苷三磷酸氢酶的编码基因SAMHD1则延长了端粒。
值得注意的是，仅仅补充dT就可以在细胞中通过端粒酶驱动强劲的端粒延长，而且胸苷三磷酸酯在体外以一种不依赖底物的方式刺激端粒酶的活性。在来自遗传性端粒生物学疾病患者的诱导多能干细胞中，dT的补充或对SAMHD1的抑制促进了端粒的恢复。这些结果证明了胸苷代谢在控制人类端粒酶和端粒长度方面的关键作用，这可能对患有致命退行性疾病的患者具有治疗作用。
据悉，人类的端粒长度与寿命和严重的疾病有关，然而端粒长度的遗传决定因素仍未完全确定。
附：英文原文
Title: Thymidine nucleotide metabolism controls human telomere length
Author: Mannherz, William, Agarwal, Suneet
Issue&Volume: 2023-03-23
Abstract: Telomere length in humans is associated with lifespan and severe diseases, yet the genetic determinants of telomere length remain incompletely defined. Here we performed genome-wide CRISPR–Cas9 functional telomere length screening and identified thymidine (dT) nucleotide metabolism as a limiting factor in human telomere maintenance. Targeted genetic disruption using CRISPR–Cas9 revealed multiple telomere length control points across the thymidine nucleotide metabolism pathway: decreasing dT nucleotide salvage via deletion of the gene encoding nuclear thymidine kinase (TK1) or de novo production by knockout of the thymidylate synthase gene (TYMS) decreased telomere length, whereas inactivation of the deoxynucleoside triphosphohydrolase-encoding gene SAMHD1 lengthened telomeres. Remarkably, supplementation with dT alone drove robust telomere elongation by telomerase in cells, and thymidine triphosphate stimulated telomerase activity in a substrate-independent manner in vitro. In induced pluripotent stem cells derived from patients with genetic telomere biology disorders, dT supplementation or inhibition of SAMHD1 promoted telomere restoration. Our results demonstrate a critical role of thymidine metabolism in controlling human telomerase and telomere length, which may be therapeutically actionable in patients with fatal degenerative diseases.
DOI: 10.1038/s41588-023-01339-5
Source: https://www.nature.com/articles/s41588-023-01339-5
Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex
本期文章：《自然—遗传学》：Online/在线发表
