February 24, 2020
Cancer biology investigator featured in Biochemistry and Molecular Biophysics seminar
Bret Freudenthal, professor of biochemistry and molecular biology at the University of Kansas Medical Center and investigator at the University of Kansas Cancer Center, is the featured speaker for the upcoming Biochemistry and Molecular Biophysics Seminar on Wednesday, Feb. 26. He will present "Mechanisms of nucleotide selection by telomerase: Implications for cancer therapy" at 4 p.m. in 120 Ackert Hall.
Telomerase protects genomic DNA by extending the protective telomere sequences found at chromosomal ends. How the telomerase active site selects canonical matched deoxyribonucleotides for telomere extension is poorly understood. To elucidate this mechanism, we determined the X-ray crystal structures of the catalytic subunit of a homolog to human telomerase reverse transcriptase, or TERT, throughout its entire catalytic cycle, including a complex poised to insert an incoming nucleotide into a telomeric sequence. Combining these structures with pre-steady-state kinetic analysis, we have assigned mechanistic roles for key active site residues with regard to telomerase fidelity and ribonucleotide insertion. Our observations with the model TERT were recapitulated in complementary studies with human telomerase to identify the telomerase steric gate residue that prevents the insertion of ribonucleotides in telomeres. From this we have obtained an understanding of how telomerase specifically selects canonical rather than noncanonical nucleotides for telomeric DNA elongation, thus protecting telomere integrity.