The Mre11-Rad50-Xrs2 (MRX) complex acts together with the Sae2 protein to initiate resection of DNA double-strand breaks (DSBs) and to regulate a checkpoint response that couples cell cycle progression with DSB repair. Sae2 supports resistance to DNA damage and downregulates the signaling activities of MRX, Tel1, and Rad53 checkpoint proteins at the sites of damage. How these functions are connected to each other is not known. Here, we describe the separation-of-function sae2-ms mutant that, similar to SAE2 deletion, upregulates MRX and Tel1 signaling activities at DSBs by reducing Mre11 endonuclease activity. However, unlike SAE2 deletion, Sae2-ms causes neither DNA damage sensitivity nor enhanced Rad53 activation, indicating that DNA damage resistance depends mainly on Sae2-mediated Rad53 inhibition. The lack of Sae2, but not the presence of Sae2-ms, impairs long-range resection and increases both Rad9 accumulation at DSBs and Rad53–Rad9 interaction independently of Mre11 nuclease activity. Altogether, these data lead to a model whereby Sae2 plays distinct functions in limiting MRX-Tel1 and Rad9 abundance at DSBs, with the control on Rad9 association playing the major role in supporting DNA damage resistance and in regulating long-range resection and checkpoint activation

Colombo, C., Menin, L., Ranieri, R., Bonetti, D., Clerici, M., & Longhese, M. (2019). Uncoupling Sae2 functions in downregulation of Tel1 and Rad53 signaling activities. GENETICS, 211(2), 515-530 [10.1534/genetics.118.301830].

Uncoupling Sae2 functions in downregulation of Tel1 and Rad53 signaling activities

Colombo, Chiara Vittoria
Primo
;
Menin, Luca
Secondo
;
Bonetti, Diego;Clerici, Michela
;
Longhese, Maria Pia
Ultimo
2019

Abstract

The Mre11-Rad50-Xrs2 (MRX) complex acts together with the Sae2 protein to initiate resection of DNA double-strand breaks (DSBs) and to regulate a checkpoint response that couples cell cycle progression with DSB repair. Sae2 supports resistance to DNA damage and downregulates the signaling activities of MRX, Tel1, and Rad53 checkpoint proteins at the sites of damage. How these functions are connected to each other is not known. Here, we describe the separation-of-function sae2-ms mutant that, similar to SAE2 deletion, upregulates MRX and Tel1 signaling activities at DSBs by reducing Mre11 endonuclease activity. However, unlike SAE2 deletion, Sae2-ms causes neither DNA damage sensitivity nor enhanced Rad53 activation, indicating that DNA damage resistance depends mainly on Sae2-mediated Rad53 inhibition. The lack of Sae2, but not the presence of Sae2-ms, impairs long-range resection and increases both Rad9 accumulation at DSBs and Rad53–Rad9 interaction independently of Mre11 nuclease activity. Altogether, these data lead to a model whereby Sae2 plays distinct functions in limiting MRX-Tel1 and Rad9 abundance at DSBs, with the control on Rad9 association playing the major role in supporting DNA damage resistance and in regulating long-range resection and checkpoint activation
No
Articolo in rivista - Articolo scientifico
Scientifica
MRX; Rad53; Rad9; Sae2; Tel1; Genetics
English
515
530
16
Colombo, C., Menin, L., Ranieri, R., Bonetti, D., Clerici, M., & Longhese, M. (2019). Uncoupling Sae2 functions in downregulation of Tel1 and Rad53 signaling activities. GENETICS, 211(2), 515-530 [10.1534/genetics.118.301830].
Colombo, C; Menin, L; Ranieri, R; Bonetti, D; Clerici, M; Longhese, M
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/222404
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