Laboratory

My lab’s long-term research program focuses on understanding how telomere maintenance and genome stability is regulated, either by telomerase or the telomerase-independent homologous recombination-based Alternative Lengthening of Telomere (ALT) mechanism.

Functional chromosome ends, or telomeres, are essential for cell survival. Telomere function is maintained by (i) telomeric shelterin proteins that mediate a protective cap structure formation, and (ii) telomere lengthening, either by the enzyme telomerase, or a recombination-based mechanism (ALT). Non-functional telomeres arise due to telomere shortening or to cap alterations, and activate DNA damage checkpoints, and cell senescence or death. Non-functional 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 or telomere complexes, telomere shortening is accelerated, and patients have premature onset of several age-related disorders and early death. Telomerase is active in ~85% of tumors, but weakly in primary cells, thus it is an attractive target for cancer cell-specific therapy.

My lab is pursuing projects to identify and characterize unique determinants of telomerase and telomere function, in recruitment and activation of telomerase to telomeres, critical steps that are impaired in premature aging telomere syndromes, and essential to the replicative immortality of cancer cells. We are also investigating the role of dyskerin, a telomerase holoenzyme component in the processing and biogenesis of a mature, functional telomerase complex, to learn more about the mechanisms that are altered in the premature aging syndrome, dyskeratosis congenita. Understanding the regulation of cell survival and immortalization by telomere maintenance and telomerase will lead to the identification of targets with potential therapeutic applications for cancer and age- or disease-related cell death.

Telomeres are prone to replication stress (slowing/stalling of the replication fork) in part due to the G-rich nature of telomeric sequences that can form secondary structures such as G-quadruplexes (G4s), the protective T- and D-loop cap structures, R-loops, and telomere compaction and attachment to the nuclear envelope. The mechanisms modulating the challenges of telomere replication are poorly understood. ALT+ cells are characterized by long telomeres and thus higher levels of telomere DNA damage and chronic replication stress compared to telomerase+ cells with shorter telomeres.

To gain a better understanding of the ALT pathway of telomere maintenance that is present in certain cancers with a high unmet medical need such as osteosarcomas, pediatric glioblastomas, other central nervous system tumors and pancreatic neuroendocrine cancers, we are interested in understanding the role of proliferating cell nuclear antigen (PCNA) and replication stress in regulating this pathway.