The Shelterin Protein TRF2 Inhibits Chk2 Activity at Telomeres in the Absence of DNA Damage

• DOI: 10.1016/j.cub.2009.03.064
• Publication Date: 2009-04-17T08:48:00Z
• Authors: Giacomo Buscemi; Laura Zannini; Enrico Fontanella; Daniele Lecis; Sofia Lisanti; Domenico Delia
• Keywords: 0301 basic medicine; Agricultural and Biological Sciences(all); Biochemistry, Genetics and Molecular Biology(all); Tumor Suppressor Proteins; Cell Cycle Proteins; DNA; Ataxia Telangiectasia Mutated Proteins; Protein Serine-Threonine Kinases; Telomere; telomeres; Cell Line; Protein Structure, Tertiary; DNA-Binding Proteins; Checkpoint Kinase 2; 03 medical and health sciences; Neoplasms; DNA damage; Animals; Humans; Telomeric Repeat Binding Protein 2; Telomerase; Cellular Senescence; DNA Damage

The shelterin complex [1] shapes and protects telomeric DNA from being processed as double strand breaks (DSBs) [2, 3]. Here we show that in human undamaged cells, a fraction of the kinase Chk2, a downstream target of ATM and mediator of checkpoint responses and senescence [4, 5], physically interacts with the shelterin subunit TRF2 and colocalizes with this complex at chromosome ends. This interaction, enhanced by TRF2 binding to telomeric DNA, inhibits the activation and senescence-induced function of Chk2 by a mechanism in which TRF2 binding to the N terminus of Chk2 surrounding Thr68 hinders the phosphorylation of this priming site. In response to radiation-induced DSBs, but not chromatin-remodelling agents, the telomeric Chk2-TRF2 binding dissociates in a Chk2 activity-dependent manner. Moreover, active Chk2 phosphorylates TRF2 and decreases its binding to telomeric DNA repeats, corroborating the evidences on the specific TRF2 relocalization in presence of DSBs [6]. Altogether, the capacity of TRF2 to locally repress Chk2 provides an additional level of control by which shelterin restrains the DNA damage response from an unwanted activation [6, 7] and may explain why TRF2 overexpression acts as a telomerase-independent oncogenic stimulus [8].