title: Physical and functional interactions between Werner syndrome helicase and mismatch-repair initiation factors.
abstract: Werner syndrome (WS) is a severe recessive disorder characterized by premature aging, cancer predisposition and genomic instability. The gene mutated in WS encodes a bi-functional enzyme called WRN that acts as a RecQ-type DNA helicase and a 3'-5' exonuclease, but its exact role in DNA metabolism is poorly understood. Here we show that WRN physically interacts with the MSH2/MSH6 (MutSalpha), MSH2/MSH3 (MutSbeta) and MLH1/PMS2 (MutLalpha) heterodimers that are involved in the initiation of mismatch repair (MMR) and the rejection of homeologous recombination. MutSalpha and MutSbeta can strongly stimulate the helicase activity of WRN specifically on forked DNA structures with a 3'-single-stranded arm. The stimulatory effect of MutSalpha on WRN-mediated unwinding is enhanced by a G/T mismatch in the DNA duplex ahead of the fork. The MutLalpha protein known to bind to the MutS alpha-heteroduplex complexes has no effect on WRN-mediated DNA unwinding stimulated by MutSalpha, nor does it affect DNA unwinding by WRN alone. Our data are consistent with results of genetic experiments in yeast suggesting that MMR factors act in conjunction with a RecQ-type helicase to reject recombination between divergent sequences.
authors: Institute of Molecular Cancer Research of the University of Zurich, Switzerland.
authors: Nurten
authors: N
authors: Saydam
authors: Radhakrishnan
authors: R
authors: Kanagaraj
authors: Tobias
authors: T
authors: Dietschy
authors: Patrick L
authors: PL
authors: Garcia
authors: Javier
authors: J
authors: Peña-Diaz
authors: Igor
authors: I
authors: Shevelev
authors: Igor
authors: I
authors: Stagljar
authors: Pavel
authors: P
authors: Janscak
mesh_terms: D020137:Base Pair Mismatch; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005090:Exodeoxyribonucleases; D006801:Humans; D000070956:MutL Proteins; D051718:MutS Homolog 2 Protein / Q000378:metabolism; D000074081:MutS Homolog 3 Protein; D017434:Protein Structure, Tertiary; D053484:RecQ Helicases / Q000737:chemistry / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D000071657:Werner Syndrome Helicase
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C078444:MSH3 protein, human; C500929:MutLalpha protein, human; D000074081:MutS Homolog 3 Protein; D004247:DNA; D005090:Exodeoxyribonucleases; C497172:MSH2 protein, human; D000070956:MutL Proteins; D051718:MutS Homolog 2 Protein; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D045643:DNA Repair Enzymes
references: Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2205-10
references: 17284601
references: J Biol Chem. 2007 Feb 2;282(5):2976-86
references: 17148452
references: FASEB J. 2002 May;16(7):757-8
references: 11978740
references: J Biol Chem. 2002 May 24;277(21):18291-302
references: 11889123
references: J Biol Chem. 2002 Jun 28;277(26):23236-45
references: 11956187
references: Mol Cell Biol. 2002 Oct;22(20):6971-8
references: 12242278
references: DNA Repair (Amst). 2002 Sep 4;1(9):719-29
references: 12509276
references: Curr Opin Genet Dev. 2003 Feb;13(1):61-9
references: 12573437
references: J Mol Biol. 2003 Jun 27;330(1):29-42
references: 12818200
references: Aging Cell. 2002 Oct;1(1):30-9
references: 12882351
references: J Biol Chem. 2003 Sep 19;278(38):36476-86
references: 12750383
references: Biol Chem. 2003 Aug;384(8):1155-64
references: 12974384
references: Oncogene. 2004 May 6;23(21):3749-56
references: 15064730
references: J Biol Chem. 2004 May 14;279(20):21169-76
references: 15026416
references: Biotechniques. 2004 May;36(5):872-6
references: 15152608
references: Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9315-20
references: 15199178
references: J Cell Physiol. 1977 Sep;92(3):365-74
references: 903377
references: Cytogenet Cell Genet. 1981;30(2):92-107
references: 7273860
references: Natl Cancer Inst Monogr. 1982;60:241-7
references: 6214719
references: Adv Exp Med Biol. 1985;190:541-6
references: 4083162
references: Proc Natl Acad Sci U S A. 1989 Aug;86(15):5893-7
references: 2762303
references: Science. 1996 Apr 12;272(5259):258-62
references: 8602509
references: Curr Biol. 1996 Sep 1;6(9):1181-4
references: 8805365
references: Cancer Res. 1997 Jul 15;57(14):2956-60
references: 9230208
references: Nat Genet. 1997 Sep;17(1):100-3
references: 9288107
references: Nat Genet. 1998 Oct;20(2):114-6
references: 9771700
references: J Biol Chem. 1998 Dec 18;273(51):34145-50
references: 9852074
references: J Biol Chem. 1999 Nov 5;274(45):32368-75
references: 10542278
references: Genes Dev. 2000 Apr 15;14(8):907-12
references: 10783163
references: Mutat Res. 2000 Jun 30;460(1):41-52
references: 10856833
references: Nature. 2000 Oct 12;407(6805):711-7
references: 11048711
references: Nat Genet. 2001 Jan;27(1):113-6
references: 11138010
references: J Biol Chem. 2001 May 11;276(19):16439-46
references: 11279038
references: FASEB J. 2001 May;15(7):1224-6
references: 11344095
references: Nucleic Acids Res. 2001 Jul 1;29(13):2843-9
references: 11433031
references: J Biol Chem. 2001 Aug 10;276(32):30031-5
references: 11325959
references: J Biol Chem. 2001 Aug 31;276(35):33233-40
references: 11441019
references: EMBO J. 2001 Oct 15;20(20):5791-801
references: 11598021
references: Nucleic Acids Res. 2001 Nov 1;29(21):4378-86
references: 11691925
references: Hum Genet. 1999 Jan;104(1):10-4
references: 10071186
references: Mol Cell. 1999 Feb;3(2):255-61
references: 10078208
references: Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3969-74
references: 10097147
references: Nucleic Acids Res. 1999 Sep 1;27(17):3557-66
references: 10446247
references: Science. 2004 Dec 10;306(5703):1951-3
references: 15591207
references: Mech Ageing Dev. 2005 Jan;126(1):79-86
references: 15610765
references: Genetics. 2005 Feb;169(2):563-74
references: 15489516
references: Curr Biol. 2005 Mar 8;15(5):470-4
references: 15753043
references: Annu Rev Biochem. 2005;74:681-710
references: 15952900
references: J Biol Chem. 2005 Jul 29;280(30):28085-94
references: 15886194
references: J Cell Sci. 2005 Sep 15;118(Pt 18):4153-62
references: 16141234
references: Nucleic Acids Res. 2005;33(18):5851-60
references: 16221978
references: J Biol Chem. 2005 Dec 9;280(49):40559-67
references: 16223718
references: Oncogene. 2006 Apr 20;25(17):2531-6
references: 16331258
references: Nat Rev Mol Cell Biol. 2006 May;7(5):335-46
references: 16612326
references: J Mol Biol. 2006 Jul 14;360(3):523-36
references: 16781730
references: Cell. 2006 Jul 28;126(2):297-308
references: 16873062
references: Mol Cell Biol. 2002 Apr;22(7):2388-97
references: 11884621