Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province 310036, China.
Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):13308-13. doi: 10.1073/pnas.1206672109. Epub 2012 Jul 30.
Oxidative stress regulates telomere homeostasis and cellular aging by unclear mechanisms. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a key mediator of many oxidative stress responses, involving GAPDH nuclear translocation and induction of cell death. We report here that GAPDH interacts with the telomerase RNA component (TERC), inhibits telomerase activity, and induces telomere shortening and breast cancer cell senescence. The Rossmann fold containing NAD(+) binding region on GAPDH is responsible for the interaction with TERC, whereas a lysine residue in the GAPDH catalytic domain is required for inhibiting telomerase activity and disrupting telomere maintenance. Furthermore, the GAPDH substrate glyceraldehyde-3-phosphate (G3P) and the nitric oxide donor S-nitrosoglutathione (GSNO) both negatively regulate GAPDH inhibition of telomerase activity. Thus, we demonstrate that GAPDH is regulated to target the telomerase complex, resulting in an arrest of telomere maintenance and cancer cell proliferation.
氧化应激通过不明机制调节端粒稳态和细胞衰老。甘油醛 3-磷酸脱氢酶（GAPDH）是许多氧化应激反应的关键介质，涉及 GAPDH 核易位和诱导细胞死亡。我们在这里报告，GAPDH 与端粒酶 RNA 成分（TERC）相互作用，抑制端粒酶活性，并诱导端粒缩短和乳腺癌细胞衰老。GAPDH 上含 NAD（+）结合区域的 Rossmann 折叠负责与 TERC 的相互作用，而 GAPDH 催化结构域中的一个赖氨酸残基对于抑制端粒酶活性和破坏端粒维持是必需的。此外，GAPDH 的底物甘油醛-3-磷酸（G3P）和一氧化氮供体 S-亚硝基谷胱甘肽（GSNO）都负调节 GAPDH 对端粒酶活性的抑制作用。因此，我们证明 GAPDH 被调控以靶向端粒酶复合物，导致端粒维持和癌细胞增殖的停滞。
