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Local activation of mammalian separase in interphase promotes double-strand break repair and prevents oncogenic transformation

Titelangaben

Hellmuth, Susanne ; Gutiérrez-Caballero, Cristina ; Llano, Elena ; Pendás, Alberto M. ; Stemmann, Olaf:
Local activation of mammalian separase in interphase promotes double-strand break repair and prevents oncogenic transformation.
In: The EMBO Journal. Bd. 37 (2018) Heft 22 . - e99184.
ISSN 1460-2075
DOI: https://doi.org/10.15252/embj.201899184

Angaben zu Projekten

Projektfinanzierung: Deutsche Forschungsgemeinschaft

Abstract

Separase halves eukaryotic chromosomes in M-phase by cleaving cohesin complexes holding sister chromatids together. Whether this essential protease functions also in interphase and/or impacts carcinogenesis remains largely unknown. Here, we show that mammalian separase is recruited to DNA double-strand breaks (DSBs) where it is activated to locally cleave cohesin and facilitate homology-directed repair (HDR). Inactivating phosphorylation of its NES, arginine methylation of its RG-repeats, and sumoylation redirect separase from the cytosol to DSBs. In vitro assays suggest that DNA damage response-relevant ATM, PRMT1, and Mms21 represent the corresponding kinase, methyltransferase, and SUMO ligase, respectively. SEPARASE heterozygosity not only debilitates HDR but also predisposes primary embryonic fibroblasts to neoplasia and mice to chemically induced skin cancer. Thus, tethering of separase to DSBs and confined cohesin cleavage promote DSB repair in G2 cells. Importantly, this conserved interphase function of separase protects mammalian cells from oncogenic transformation.

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Publikationsform: Artikel in einer Zeitschrift
Begutachteter Beitrag: Ja
Keywords: cohesin; DNA double-strand breaks; homology-directed repair; posttranslational modifications; separase; SISTER-CHROMATID COHESION; DNA-DAMAGE; DEPENDENT REMOVAL; PROTEIN; GENOME; CELLS; SUMO; OVEREXPRESSION; CLEAVAGE; DOMAIN
Institutionen der Universität: Fakultäten
Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften
Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Biologie
Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Biologie > Lehrstuhl Genetik
Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Biologie > Lehrstuhl Genetik > Lehrstuhl Genetik - Univ.-Prof. Dr. Olaf Stemmann
Profilfelder > Advanced Fields > Molekulare Biowissenschaften
Profilfelder
Profilfelder > Advanced Fields
Titel an der UBT entstanden: Ja
Themengebiete aus DDC: 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften; Biologie
Eingestellt am: 26 Feb 2020 09:15
Letzte Änderung: 15 Jun 2023 11:56
URI: https://eref.uni-bayreuth.de/id/eprint/54402