Functional Analysis of TRF1 Phosphorylation in Telomere Maintenance, Cell Cycle Regulation, and the DNA Damage Response

Abstract

<p><h2> </h2></p> <p>Telomeres are protein-DNA complexes found at the ends of human chromosomes. The function of telomeres is to protect chromosome ends from being recognized as damaged DNA. This protection is essential in preventing the erosion of telomeres, which has been shown to lead to genomic instability, a hallmark of cancer and aged cells. Precise regulation of telomere length and function is crucial to cell survival, and defects in this regulation are related to tumorigenesis and aging related disorders. The proteins that bind telomere DNA play an indispensable role in telomere maintenance. TRF1, <em>t</em>elomere <em>r</em>epeat binding <em>f</em>actor 1, is a protein that directly binds to mammalian telomeric DNA and participates in regulating telomere length. Post-translational modifications, such as phosphorylation, have been shown to modulate TRF1 function. The results presented here demonstrate that two phosphorylation sites on TRF1, S367 and T371, are involved in regulating the function and localization of TRF1. TRF1 S367 is phosphorylated by ATM, and this phosphorylation removes TRF1 from telomere DNA and directs TRF1 to sites of proteasome degradation. On the other hand, the phosphorylation of TRF1 at T371 prevents the association of TRF1 with telomere DNA but also protects TRF1 from degradation. We have demonstrated that the phosphorylation of T371 by CDK1 is important for the resolution of sister chromatids in mitosis. In interphase cells, in response to the induction of DNA damage, TRF1 phosphorylated at T371 is recruited to sites of damage and is involved in promoting efficient homologous recombination and in conferring checkpoint activation and cell survival. The work presented within this thesis sheds light on the regulation of TRF1 function by phosphorylation events and reveals novel functions of TRF1.</p>