Elucidation of the consequence of telomere single-stand overhang, G-tail, in biology, and application to age-related disease

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(1) Conditiona deletion of mouse Potla induces a DNA damage response at telomeres, resulting in p53-dependent replicative senescence. Potla-deficient cells exhibit overall telomere length and 3' overhang elongation as well as aberrant homologous recombination (HR) at telomeres, manifested as increased telomere sister chromatid exchanges and formation of telomere circles.(2) We found that G-tail length were reduce in fibroblats, hetatocytes and HUVEC cells with cellular senescence. When forced expression of hTERT gene into these human normal cells, both telomere G-tail and total telomere length were elongated.(3) The wild-type FN-tankyrase 1 increased the G-tail size to 134% of the mock cell line. FN-tank-ARC IVmut-ΔARC V also elongated the G-tail to 123% of the mock line. Collectively, reduced POT1 binding and increased G-tail length would reflect higher accessibility of telomerase to telomeres.Further study of telomere associated proteins including shelterin complex (TRF1, TRF2, TIN2, PTOP, POT1, RAP1, Apollo) is important for the elucidation of genomic instability as well as genomic integrity in human disease such as cancer and aging.