Abstract
BackgroundThe main function of telomerase is at the telomeres but under adverse conditions telomerase can bind to internal regions causing deleterious effects as observed in cancer cells.ResultsBy mapping the global occupancy of the catalytic subunit of telomerase (Est2) in the budding yeast Saccharomyces cerevisiae, we reveal that it binds to multiple guanine-rich genomic loci, which we termed “non-telomeric binding sites” (NTBS). We characterize Est2 binding to NTBS. Contrary to telomeres, Est2 binds to NTBS in G1 and G2 phase independently of Est1 and Est3. The absence of Est1 and Est3 renders telomerase inactive at NTBS. However, upon global DNA damage, Est1 and Est3 join Est2 at NTBS and telomere addition can be observed indicating that Est2 occupancy marks NTBS regions as particular risks for genome stability.ConclusionsOur results provide a novel model of telomerase regulation in the cell cycle using internal regions as “parking spots” of Est2 but marking them as hotspots for telomere addition.
Highlights
The main function of telomerase is at the telomeres but under adverse conditions telomerase can bind to internal regions causing deleterious effects as observed in cancer cells
Studies in yeast and human suggest that telomerase components are not associated with the telomere throughout the cell cycle and the catalytic subunit of telomerase itself or associated proteins perform a function at internal regions [8, 20,21,22,23,24,25,26,27]
Our work provides a genomic map of potentially vulnerable internal sites where telomerase subunits can bind
Summary
The main function of telomerase is at the telomeres but under adverse conditions telomerase can bind to internal regions causing deleterious effects as observed in cancer cells. Single molecule imaging showed that TLC1 remains in the nucleoplasm in G1/S phase and the nucleolus in G2/M phase This segregation is lost under DNA damage conditions in rad52Δ cells in which TLC1 localizes at DSBs and leads to de novo telomere addition. Multiple proteins such as Pif, Cdc, and the SUMO ligase Siz are involved in regulating telomerase action at DSBs [24,25,26, 28,29,30,31]. These sites contain a bipartite structure, a global prediction and validation of SiRTAs under different genetic and biochemical conditions is still missing
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