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Uncoupling Sae2 Functions in Downregulation of Tel1 and Rad53 Signaling Activities.
Genetics. 2019 02; 211(2):515-530.G

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.

Authors+Show Affiliations

Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca, 20126 Milan, Italy.Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca, 20126 Milan, Italy.Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca, 20126 Milan, Italy.Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca, 20126 Milan, Italy.Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca, 20126 Milan, Italy mariapia.longhese@unimib.it michela.clerici@unimib.it.Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca, 20126 Milan, Italy mariapia.longhese@unimib.it michela.clerici@unimib.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30538107

Citation

Colombo, Chiara Vittoria, et al. "Uncoupling Sae2 Functions in Downregulation of Tel1 and Rad53 Signaling Activities." Genetics, vol. 211, no. 2, 2019, pp. 515-530.
Colombo CV, Menin L, Ranieri R, et al. Uncoupling Sae2 Functions in Downregulation of Tel1 and Rad53 Signaling Activities. Genetics. 2019;211(2):515-530.
Colombo, C. V., Menin, L., Ranieri, R., Bonetti, D., Clerici, M., & Longhese, M. P. (2019). Uncoupling Sae2 Functions in Downregulation of Tel1 and Rad53 Signaling Activities. Genetics, 211(2), 515-530. https://doi.org/10.1534/genetics.118.301830
Colombo CV, et al. Uncoupling Sae2 Functions in Downregulation of Tel1 and Rad53 Signaling Activities. Genetics. 2019;211(2):515-530. PubMed PMID: 30538107.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Uncoupling Sae2 Functions in Downregulation of Tel1 and Rad53 Signaling Activities. AU - Colombo,Chiara Vittoria, AU - Menin,Luca, AU - Ranieri,Riccardo, AU - Bonetti,Diego, AU - Clerici,Michela, AU - Longhese,Maria Pia, Y1 - 2018/12/11/ PY - 2018/10/16/received PY - 2018/12/09/accepted PY - 2018/12/13/pubmed PY - 2019/3/29/medline PY - 2018/12/13/entrez KW - MRX KW - Rad53 KW - Rad9 KW - Sae2 KW - Tel1 SP - 515 EP - 530 JF - Genetics JO - Genetics VL - 211 IS - 2 N2 - 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. SN - 1943-2631 UR - https://www.unboundmedicine.com/medline/citation/30538107/Uncoupling_Sae2_Functions_in_Downregulation_of_Tel1_and_Rad53_Signaling_Activities_ L2 - http://www.genetics.org/cgi/pmidlookup?view=long&pmid=30538107 DB - PRIME DP - Unbound Medicine ER -