Foster CA, Fraser S, Karakas B, Monda D, Gipson E, Brown LK, Zhang J, Hickman D, Villeponteau B, Piatyszek MA, Lee Y-J, Andrews WH, Nguyen D, Fleming J, Townsend J, Coelho E, Ardelean R, Kishpaugh A, Villaluz F, Chatuguru R, Mohammadpour H, Briggs LA.

Telomeres are chromosomal caps that prevent genomic instability and protect chromosomal integrity. When cells divide, telomeres shorten due to the "end replication problem". Decreased telomere length is associated with cellular senescence (aging), as older cells show markedly shorter telomeres. A predominant hypothesis between telomere length and aging is that the relationship is causative rather than correlative, i.e. decreased telomere length causes aging, or at least several of the main symptoms of it. We are seeking to find ways to actively elongate telomere length or prevent their shortening in human somatic cells. Telomerase is a ribonucleoprotein made up of an RNA component (hTR) and a protein component (hTERT) that replicates the telomeric repeat (TTAGGG) at the ends of the chromosomes. The RNA component, hTR, is readily found in telomerase negative cells while the protein component, hTERT, is the limiting factor in telomerase activity. We believe hTERT is repressed by one or more as yet undetermined transcription factors acting upon the hTERT promoter.

Sierra Sciences has done very extensive work (more than has ever been done before) to bash the hTERT minimal promoter (-258 bp from the start ATG) in a transient expression system in an attempt to determine these factors. We have identified several sites within this region which are potential activation or repression sites. The major repressor site, which we call Site C, was inserted into the SV40 promoter and shown to also repress this promoter. We also identified bases -107 to -37 as the minimal minimum region needed for activation and repression of the telomerase promoter, and we call this region the minimized minimal promoter (MMP).