(1) 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, including determinants of enzyme processivity, telomerase domains mediating recruitment to telomeres, and post-translational modifications of telomerase components. 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.

(2) 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 structures, R-loops, and telomere compaction and attachment to the nuclear envelope. The mechanisms modulating the challenges of telomere replication are poorly understood. Telomere replication stress represents a therapeutic opportunity for the treatment of cancers, consistent with ongoing efforts to exploit genome-wide replicative stress to treat various cancers. For example, homologous recombinational repair defects (such as impaired BRCA1) cause hypersensitivity of telomerase+ human cancer cells to inhibitors of telomere replication. However, 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. Thus, we propose that targeting telomere recombination and replication may be more efficient in ALT+ cancers such as pediatric glioblastomas.

Towards the end, we are interested in understanding the role of proliferating cell nuclear antigen (PCNA) and sumoylated PCNA in the regulation of replication stress at telomeres, and telomere maintenance, particularly in the recombination-based mechanism of telomere maintenance.
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