One requirement for cell proliferation and survival is telomere integrity; unstable telomeres lead to chromosome degradation, end-to-end chromosome fusions, and the activation of DNA damage checkpoints. Telomeres, the ends of chromosomes, serve as protective caps that prevent chromosomes from fusing together and causing DNA rearrangements that can lead to karyotypic changes and genomic instability. Conventional semi-conservative DNA replication does not allow for the completion of chromosome ends, so telomere length is predicted to decrease with successive rounds of cell division and replication. Telomere integrity is maintained by (i) telomeric proteins which mediate the formation of a protective cap structure, and (ii) primarily the enzyme telomerase, or a recombination pathway termed alternative lengthening of telomeres (ALT). Human telomerase is composed of a catalytic subunit (hTERT) and an RNA component (hTR) that provides the template for the synthesis of repeated G-rich d(TTAGGG)n telomere sequences. Telomere integrity can be jeopardized by extensive telomere shortening in the absence of a telomere maintenance mechanism, or by alteration of the protective cap. Dysfunctional telomeres may contribute to the development of aging phenotypes, such as vascular disease, poor wound healing, and immunosenescence. In the genetic syndrome dyskeratosis congenita, caused by defects in the telomerase complex, telomere shortening is accelerated, and patients have premature onset of several age-related disorders and early death. Furthermore, ectopic expression of hTERT in telomerase-negative primary cells constitutively expressing hTR induces telomerase activity, lengthens telomeres and extends cellular life span, but does not induce changes associated with malignant transformation. Concomitant alteration of key cellular proteins (p53, pRb, H-Ras) can convert primary cells into tumorigenic cells, indicating that telomerase activation and telomere maintenance are critical steps for immortalization and tumorigenesis. Notably, telomerase is expressed in 85% of human cancers. Moreover, inhibiting telomerase results in telomere loss, chromosome damage, and cell death of various human cancer cell lines, validating the search for telomerase inhibitors as anticancer therapies. Understanding the regulation of cell survival and tumorigenesis by telomere maintenance and telomerase will lead to the identification of targets with potential therapeutic applications to prevent age- or disease-related cell death, and for inducing cancer cell death.
Dr. Autexier’s research aims to establish a molecular base for the development of anticancer therapies that target telomerase or telomere integrity and the efficacious treatments of age-related cell death. Studies in the lab are focused on 1. characterizing the mechanisms that regulate telomerase, telomere length and cell survival, including associated proteins, enzyme processivity, alternative splicing of the TERT telomerase component, and post-translational modifications and 2. on evaluating the principles of anti-cancer strategies that target telomerase or telomere integrity, by validating novel ligands which stabilize G-quadruplex structures at telomeres, and through studies to understand the regulation of telomere maintenance by recombination in telomerase-negative cancer cells and in telomerase-positive cancer cells in which telomere function is targeted.
Course coordinator: Cellular and Molecular Biology of Aging course ANAT541B
Undergraduate: Cellular and Molecular Biology of Aging course ANAT541B
Undergraduate: Biochemistry of Membranes ANAT/BIOC-458B
Graduate: Cell and Developmental Biology ANAT690D
Graduate: Special Topics in Molecular and Cellular, Biology EXMD616A
Graduate: Molecular Control of Cell Growth EXMD607B