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].

The shelterin protein TRF2 inhibits Chk2 activity at telomeres in the absence of DNA damage / G. Buscemi, L. Zannini, E. Fontanella, D. Lecis, S. Lisanti, D. Delia. - In: CURRENT BIOLOGY. - ISSN 0960-9822. - 19:10(2009), pp. 874-879. [10.1016/j.cub.2009.03.064]

The shelterin protein TRF2 inhibits Chk2 activity at telomeres in the absence of DNA damage

G. Buscemi;
2009

Abstract

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].
No
English
DNA
Settore BIO/11 - Biologia Molecolare
Articolo
Esperti anonimi
2009
Cell Press
19
10
874
879
6
Pubblicato
Periodico con rilevanza internazionale
info:eu-repo/semantics/article
The shelterin protein TRF2 inhibits Chk2 activity at telomeres in the absence of DNA damage / G. Buscemi, L. Zannini, E. Fontanella, D. Lecis, S. Lisanti, D. Delia. - In: CURRENT BIOLOGY. - ISSN 0960-9822. - 19:10(2009), pp. 874-879. [10.1016/j.cub.2009.03.064]
none
Prodotti della ricerca::01 - Articolo su periodico
6
262
Article (author)
Periodico con Impact Factor
G. Buscemi, L. Zannini, E. Fontanella, D. Lecis, S. Lisanti, D. Delia
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/227843
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