Abstract 3214: C-strand fill-in at human telomeres requires lagging strand synthesis machinery and is essential for maintaining functional telomeres

Abstract

Abstract Telomeric single-stranded G-overhangs are required for protecting chromosome ends and for telomerase elongation of telomeres. However, the molecular mechanism for G-overhang generation at human telomeres is unclear. We report here that G-overhangs undergo cell cycle-regulated dynamic changes independent of telomerase activity. G-overhangs are lengthened during S phase due to extensive C-strand resection, and shortened at G2 phase as a result of C-strand fill-in. This delayed C-strand fill-in is mediated by lagging-strand polymerases and regulated by cyclin-dependent kinase 1. Inhibiting C-strand fill-in induces telomere DNA damage response and a G2 arrest, suggesting a critical role of proper G-overhang generation in maintaining genome stability. In addition, the last nucleotide at C-strand remains precisely defined throughout the cell cycle. Our results indicate that both C-strand resection and fill-in are strictly regulated during the cell cycle to ensure proper G-overhang generation, and unveil an essential role of C-stand fill-in in maintaining functional telomeres. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3214.