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Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):13308-13. doi: 10.1073/pnas.1206672109. Epub 2012 Jul 30.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component.

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1
Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province 310036, China.

Abstract

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.

PMID:
22847419
PMCID:
PMC3421169
DOI:
10.1073/pnas.1206672109
[Indexed for MEDLINE]
Free PMC Article
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