Department of Biochemistry & Molecular Genetics and the
O’Neal Comprehensive Cancer Center
School of Medicine
University of Alabama at Birmingham.
Understanding telomerase regulation is important for cancer, aging, tissue regeneration, senescence, and telomere-based diseases.
Despite its importance in these fundamental processes, we still know relatively little about telomerase regulation.
Please visit the menus at the top for more details about our research and future directions, or see below for more information.
Tumor cells divide perpetually, underpinning their ability to cause fatal disease. The vast majority of cancers rely on a key set of genes that support this indefinite growth; these genes code for the enzyme telomerase.
The ends of our chromosomes are capped by specialized protein-DNA structures called telomeres that protect our genome. Telomerase is an enzyme that maintains the length of telomeres.
In the absence of telomerase, chromosome ends naturally shorten with each cell division. This gradual shortening eventually causes the cells to stop dividing and is actually a normal aspect of mammalian aging. In most normal adult cells, telomerase is not expressed, telomeres shorten, and the organism ages.
In contrast, the expression of telomerase in normal stem cells, and also in most cancer cells, effectively counteracts telomere shortening. This forestalls aging, and allows for indefinite cellular growth.
Mutations in genes for telomerase cause a wide spectrum of disorders. Studying telomerase provides key insights into the mechanisms of these short-telomere diseases, as well as cancer and aging.
Telomerase is a multi-subunit enzyme complex containing a reverse transcriptase (TERT) that copies RNA into DNA. To make this copy, TERT uses an RNA template called hTR, also contained in the telomerase complex. hTR contains a short stretch of telomeric sequence, which is then copied by TERT onto the ends of the chromosomes to extend the telomeres.
The regulation of telomerase expression and function is now known to differ in many normal and pathogenic contexts. One broad aim of the lab is to elucidate the mechanisms governing telomerase function. In the course of pursuing this aim, our research uncovered novel epigenetic relationships between DNA methylation and polycomb repressive complex 2 (PRC2).
The PRC2 enzyme complex is responsible for tri-methylating lysine 27 of the histone 3 protein (H3K27me3). This epigenetic mark is strongly associated with gene silencing. PRC2-mediated gene silencing is essential during development to limit the expression of genes associated with later developmental stages. Along with H3K9me3 and DNA methylation on cytosines (5mC), PRC2 is one of the major cellular components of epigenetic silencing.
PRC2 is a multi-subunit enzyme complex comprised of the obligate members EZH2 (the catalytic subunit) as well as the scaffolding and recruitment partners EED and SUZ12. The enzyme complex typically has a number of additional protein partners that confer unique properties in vivo.
The occurrence of several of these PRC2 accessory proteins are mutually exclusive with one another in the complex, and appear to define critical biological parameters such as recruitment to chromatin.
The majority of our research is on telomerase and PRC2. We take both molecular and functional genomics approach to study these enzymes. Our results have revealed novel insights beyond telomerase and telomeres, including potential new cancer prognostics as well as potential new tumor suppressors and oncogenes in a number of cancers.
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