title: KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress.
abstract: During the recent years lysine methyltransferase Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) has emerged as an important regulator of different transcription factors. In this study, we report a novel function for Set7/9 as a critical co-activator of E2 promoter-binding factor 1 (E2F1)-dependent transcription in response to DNA damage. By means of various biochemical, cell biology, and bioinformatics approaches, we uncovered that cell-cycle progression through the G1/S checkpoint of tumour cells upon DNA damage is defined by the threshold of expression of both E2F1 and Set7/9. The latter affects the activity of E2F1 by indirectly modulating histone modifications in the promoters of E2F1-dependent genes. Moreover, Set7/9 differentially affects E2F1 transcription targets: it promotes cell proliferation via expression of the CCNE1 gene and represses apoptosis by inhibiting the TP73 gene. Our biochemical screening of the panel of lung tumour cell lines suggests that these two factors are critically important for transcriptional upregulation of the CCNE1 gene product and hence successful progression through cell cycle. These findings identify Set7/9 as a potential biomarker in tumour cells with overexpressed E2F1 activity.
authors.affiliation: 1] Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK [2] Molecular Pharmacology Laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg 190013, Russia.
authors.forename: L
authors.initials: L
authors.lastname: Lezina
authors.affiliation: Molecular Pharmacology Laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg 190013, Russia.
authors.forename: V
authors.initials: V
authors.lastname: Aksenova
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK.
authors.forename: T
authors.initials: T
authors.lastname: Ivanova
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK.
authors.forename: N
authors.initials: N
authors.lastname: Purmessur
authors.affiliation: MRC Toxicology Unit, Leicester LE1 9HN, UK.
authors.forename: A V
authors.initials: AV
authors.lastname: Antonov
authors.affiliation: Molecular Pharmacology Laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg 190013, Russia.
authors.forename: D
authors.initials: D
authors.lastname: Tentler
authors.affiliation: Molecular Pharmacology Laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg 190013, Russia.
authors.forename: O
authors.initials: O
authors.lastname: Fedorova
authors.affiliation: Molecular Pharmacology Laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg 190013, Russia.
authors.forename: A V
authors.initials: AV
authors.lastname: Garabadgiu
authors.affiliation: B.S.R.C. 'Alexander Fleming', Varkiza 16602, Greece.
authors.forename: I
authors.initials: I
authors.lastname: Talianidis
authors.affiliation: 1] Molecular Pharmacology Laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg 190013, Russia [2] MRC Toxicology Unit, Leicester LE1 9HN, UK [3] Faculty of Medicine, University of Rome 'Tor Vergata', Rome 00133, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Melino
authors.affiliation: 1] Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK [2] Molecular Pharmacology Laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg 190013, Russia [3] Gene Expression Laboratory, Institute of Cytology, Saint-Petersburg 194064, Russia.
authors.forename: N A
authors.initials: NA
authors.lastname: Barlev
mesh_terms: D045744:Cell Line, Tumor; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004249:DNA Damage; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D044127:Epigenesis, Genetic; D059585:G1 Phase Cell Cycle Checkpoints; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000401:mortality; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014158:Transcription, Genetic
chemical_list: D019927:Cyclin E; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2