This project explores the role of a protein dubbed GAPDH in cancer cells. The results will provide evidence for novel strategies to control cancer cell immortality by targeting the mechanism of telomerase maintenance of chromosome end.
GAPDH is a house-keeping enzyme in every normal cell of human body. But GAPDH is increased significantly and goes into the nucleus in cancer cells with unknown function.
We have previously demonstrated that in the nucleus of cancer cells, GAPDH binds DNA at the chromosome ends (telomeres) where GAPDH inhibits telomerase, an enzyme that is required for telomere maintenance and cancer cell immorality.
The gaol of this study is to define a protein structure on GAPDH to mediate GAPDH inhibition of telomerase in breast cancer cells, with the ultimate hope of developing strategies to facilitate the GAPDH inhibitory effect on breast cancer cells.
For the first time, we have carried out experiments and demonstrated that GAPDH assumes a particular pocket on the protein surfaces that holds telomere DNA. This telomere DNA binding structure (dubbed T fold) has been located in the N-terminal region of GAPDH.
To find out if GAPDH-induced telomerase inhibition is mediated by specific amino acid motifs, we engineered the protein by changing amino acid residues. A mutant of GAPDH with a single amino acid mutation in the C-terminal region of GAPDH has been demonstrated to fail GAPDH inhibition of telomerase, suggesting a novel mechanism to regulate GAPDH inhibition of telomerase in cancer.