Dipartimento di Biologia e Biotecnologie, Sapienza Università di Roma, Italy.
Cancer Signaling and Epigenetics Program-Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA, USA.
FEBS Lett. 2022 Jan;596(1):42-52. doi: 10.1002/1873-3468.14240. Epub 2021 Dec 5.
Mutations in many genes that control the expression, the function, or the stability of telomerase cause telomere biology disorders (TBDs), such as dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia. Mutations in a subset of the genes associated with TBDs cause reductions of the telomerase RNA moiety hTR, thus limiting telomerase activity. We have recently found that loss of the trimethylguanosine synthase TGS1 increases both hTR abundance and telomerase activity and leads to telomere elongation. Here, we show that treatment with the S-adenosylmethionine analog sinefungin inhibits TGS1 activity, increases the hTR levels, and promotes telomere lengthening in different cell types. Our results hold promise for restoring telomere length in stem and progenitor cells from TBD patients with reduced hTR levels.
许多控制端粒酶表达、功能或稳定性的基因发生突变会导致端粒生物学紊乱（TBD），如先天性角化不良、肺纤维化和再生障碍性贫血。与 TBD 相关的一组基因中的突变会导致端粒酶 RNA 部分 hTR 的减少，从而限制端粒酶的活性。我们最近发现，三甲基鸟苷合酶 TGS1 的缺失会增加 hTR 的丰度和端粒酶的活性，并导致端粒延长。在这里，我们表明，使用 S-腺苷甲硫氨酸类似物 sinefungin 处理可以抑制 TGS1 的活性，增加 hTR 的水平，并促进不同细胞类型中端粒的延长。我们的研究结果为恢复 TBD 患者中 hTR 水平降低的干细胞和祖细胞的端粒长度提供了希望。
