title: E2F1 responds to ultraviolet radiation by directly stimulating DNA repair and suppressing carcinogenesis.
abstract: In response to DNA damage, the E2F1 transcription factor is phosphorylated at serine 31 (serine 29 in mouse) by the ATM or ATR kinases, which promotes E2F1 protein stabilization. Phosphorylation of E2F1 also leads to the recruitment of E2F1 to sites of DNA damage, where it functions to enhance DNA repair. To study the role of this E2F1 phosphorylation event in vivo, a knock-in mouse model was generated, in which serine 29 was mutated to alanine. The S29A mutation impairs E2F1 stabilization in response to ultraviolet (UV) radiation and doxorubicin treatment, but has little effect on the expression of E2F target genes. The apoptotic and proliferative responses to acute UV radiation exposure are also similar between wild-type and E2f1(S29A/) (S29A) mice. As expected, the S29A mutation prevents E2F1 association with damaged DNA and reduces DNA repair efficiency. Moreover, E2f1(S29A/) (S29A) mice display increased sensitivity to UV-induced skin carcinogenesis. This knock-in mouse model thus links the ability of E2F1 to directly promote DNA repair with the suppression of tumor development.
authors.affiliation: Authors' Affiliations: Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Science Park; and The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
authors.forename: Anup Kumar
authors.initials: AK
authors.lastname: Biswas
authors.affiliation: Authors' Affiliations: Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Science Park; and The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TexasAuthors' Affiliations: Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Science Park; and The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
authors.forename: David L
authors.initials: DL
authors.lastname: Mitchell
authors.affiliation: Authors' Affiliations: Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Science Park; and The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TexasAuthors' Affiliations: Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Science Park; and The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas djohnson@mdanderson.org.
authors.forename: David G
authors.initials: DG
authors.lastname: Johnson
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D050687:E2F1 Transcription Factor / Q000502:physiology*; D055879:Gene Knock-In Techniques; D016147:Genes, Tumor Suppressor; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D061251:Primary Cell Culture; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D021381:Protein Transport; D012878:Skin Neoplasms / Q000235:genetics*; D014466:Ultraviolet Rays
chemical_list: D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse
references.citation: Cancer Res. 2012 Jan 1;72(1):13-7
references.pmid: 22180494
references.citation: Nat Genet. 1998 Apr;18(4):360-4
references.pmid: 9537419
references.citation: Nat Cell Biol. 2003 Jun;5(6):552-8
references.pmid: 12766778
references.citation: Int J Mol Sci. 2012 Oct 19;13(10):13554-68
references.pmid: 23202967
references.citation: Nucleic Acids Res. 1999 Jan 15;27(2):491-5
references.pmid: 9862970
references.citation: Mol Cell Biol. 2010 Jan;30(2):524-36
references.pmid: 19917728
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14025-9
references.pmid: 8943054
references.citation: Oncogene. 2007 May 24;26(24):3572-81
references.pmid: 17173070
references.citation: Nat Protoc. 2008;3(5):799-810
references.pmid: 18451788
references.citation: EMBO Rep. 2008 Mar;9(3):252-9
references.pmid: 18202719
references.citation: Trends Mol Med. 2013 Feb;19(2):89-98
references.pmid: 23219173
references.citation: Cell. 1996 May 17;85(4):549-61
references.pmid: 8653790
references.citation: J Biol Chem. 2004 Dec 24;279(52):54140-52
references.pmid: 15494392
references.citation: Genes Dev. 2001 Jul 15;15(14):1833-44
references.pmid: 11459832
references.citation: Nucleic Acids Res. 2011 Mar;39(4):1390-7
references.pmid: 20972224
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13948-53
references.pmid: 11707578
references.citation: J Biol Chem. 2000 Apr 14;275(15):10887-92
references.pmid: 10753885
references.citation: J Biol Chem. 2004 Jul 16;279(29):30830-5
references.pmid: 15123636
references.citation: Nat Rev Cancer. 2001 Oct;1(1):22-33
references.pmid: 11900249
references.citation: EMBO J. 2000 Feb 15;19(4):662-71
references.pmid: 10675335
references.citation: Curr Mol Med. 2006 Nov;6(7):739-48
references.pmid: 17100600
references.citation: Oncogene. 2005 Apr 7;24(15):2449-60
references.pmid: 15735727
references.citation: Nat Cell Biol. 2003 Jul;5(7):655-60
references.pmid: 12833065
references.citation: Nat Cell Biol. 2007 Jun;9(6):683-90
references.pmid: 17486112
references.citation: J Biol Chem. 2010 Jun 18;285(25):19308-15
references.pmid: 20413589
references.citation: Curr Mol Med. 2006 Nov;6(7):731-8
references.pmid: 17100599
references.citation: EMBO J. 2006 Mar 8;25(5):1046-57
references.pmid: 16482218
references.citation: DNA Repair (Amst). 2009 Jul 4;8(7):795-802
references.pmid: 19376752
references.citation: Cell Cycle. 2011 Apr 15;10(8):1287-94
references.pmid: 21512314
references.citation: Nat Rev Cancer. 2009 Nov;9(11):785-97
references.pmid: 19851314
references.citation: Nat Protoc. 2008;3(5):915-22
references.pmid: 18451799
references.citation: Cancer Cell. 2009 Mar 3;15(3):184-94
references.pmid: 19249677
references.citation: Cancer Res. 2002 Jun 1;62(11):3276-81
references.pmid: 12036945
references.citation: Mol Cell Biol. 2003 May;23(9):3287-304
references.pmid: 12697828
references.citation: Mol Cell Biol. 1999 May;19(5):3704-13
references.pmid: 10207094
references.citation: Cell Cycle. 2005 Jul;4(7):930-9
references.pmid: 15917652
references.citation: DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1071-9
references.pmid: 15279795
references.citation: Cell. 1996 May 17;85(4):537-48
references.pmid: 8653789
references.citation: Genes Dev. 2004 Mar 15;18(6):673-86
references.pmid: 15075294