title: Role of SUMO:SIM-mediated protein-protein interaction in non-homologous end joining.
abstract: Although post-translational modifications by the small ubiquitin-like modifiers (SUMO) are known to be important in DNA damage response, it is unclear whether they have a role in double-strand break (DSB) repair by non-homologous end joining (NHEJ). Here, we analyzed various DSB repair pathways upon inhibition of SUMO-mediated protein-protein interactions using peptides that contain the SUMO-interaction motif (SIM) and discriminate between mono- and SUMO-chain modifications. The SIM peptides specifically inhibit NHEJ as shown by in vivo repair assays and radio-sensitivity of cell lines deficient in different DSB repair pathways. Furthermore, mono-SUMO, instead of SUMO-chain, modifications appear to be involved in NHEJ. Immunoprecipitation experiments also showed that the SIM peptide interacted with SUMOylated Ku70 after radiation. This study is the first to show an important role for SUMO:SIM-mediated protein-protein interactions in NHEJ, and provides a mechanistic basis for the role of SIM peptide in sensitizing genotoxic stress of cancer cells.
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Li
authors.forename: J M
authors.initials: JM
authors.lastname: Stark
authors.forename: D J
authors.initials: DJ
authors.lastname: Chen
authors.forename: D K
authors.initials: DK
authors.lastname: Ann
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
mesh_terms: D020816:Amino Acid Motifs; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011836:Radiation Tolerance / Q000187:drug effects; D025842:SUMO-1 Protein / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D010455:Peptides; D025842:SUMO-1 Protein
references.citation: Mutat Res. 2001 Sep 1;480-481:37-50
references.pmid: 11506797
references.citation: DNA Repair (Amst). 2006 Sep 8;5(9-10):1021-9
references.pmid: 16807135
references.citation: Biochem Biophys Res Commun. 2008 Feb 1;366(1):263-8
references.pmid: 18062920
references.citation: Nature. 1995 Jan 5;373(6509):78-81
references.pmid: 7800043
references.citation: Nat Protoc. 2006;1(5):2315-9
references.pmid: 17406473
references.citation: DNA Repair (Amst). 2006 May 10;5(5):534-43
references.pmid: 16531125
references.citation: Pharmacol Rev. 2004 Jun;56(2):185-229
references.pmid: 15169927
references.citation: EMBO J. 2007 Sep 19;26(18):4089-101
references.pmid: 17762865
references.citation: EMBO Rep. 2008 Jan;9(1):91-6
references.pmid: 18064046
references.citation: Acta Biochim Pol. 2003;50(4):891-908
references.pmid: 14739985
references.citation: Mol Cell Biol. 2006 Jan;26(1):131-9
references.pmid: 16354685
references.citation: PLoS Genet. 2008 Jun 27;4(6):e1000110
references.pmid: 18584027
references.citation: Cell Cycle. 2008 May 15;7(10):1321-5
references.pmid: 18418068
references.citation: EMBO J. 2002 Mar 15;21(6):1456-64
references.pmid: 11889051
references.citation: Nat Cell Biol. 2006 Nov;8(11):1284-90
references.pmid: 17013376
references.citation: Methods Enzymol. 2000;327:283-96
references.pmid: 11044991
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4777-82
references.pmid: 15738391
references.citation: Methods Enzymol. 2006;409:524-40
references.pmid: 16793422
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 5;101(40):14373-8
references.pmid: 15388847
references.citation: Annu Rev Cell Dev Biol. 2006;22:159-80
references.pmid: 16753028
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18597-602
references.pmid: 17124166
references.citation: J Biol Chem. 2005 Dec 2;280(48):40122-9
references.pmid: 16204249
references.citation: J Biol Chem. 2007 Nov 23;282(47):34167-75
references.pmid: 17728242
references.citation: EMBO J. 1998 Jan 2;17(1):61-70
references.pmid: 9427741
references.citation: Mol Cell Biol. 2005 Jan;25(1):185-96
references.pmid: 15601841
references.citation: EMBO J. 2007 Sep 19;26(18):4102-12
references.pmid: 17762864
references.citation: J Biol Chem. 2007 Nov 23;282(47):34176-84
references.pmid: 17848550
references.citation: J Biol Chem. 2001 Sep 21;276(38):35368-74
references.pmid: 11451954
references.citation: Cancer Res. 2004 Mar 15;64(6):2096-104
references.pmid: 15026349
references.citation: Nucleic Acids Res. 1997 Mar 15;25(6):1162-9
references.pmid: 9092625
references.citation: Mol Cell Biol. 2006 Mar;26(5):1786-94
references.pmid: 16478998
references.citation: Nature. 2002 Sep 26;419(6905):411-5
references.pmid: 12353039
references.citation: J Cell Biol. 1999 Sep 6;146(5):905-16
references.pmid: 10477747
references.citation: Annu Rev Biochem. 2004;73:39-85
references.pmid: 15189136
references.citation: J Biol Chem. 1998 Mar 6;273(10):5858-68
references.pmid: 9488723