title: Mms1 and Mms22 stabilize the replisome during replication stress.
abstract: Mms1 and Mms22 form a Cul4(Ddb1)-like E3 ubiquitin ligase with the cullin Rtt101. In this complex, Rtt101 is bound to the substrate-specific adaptor Mms22 through a linker protein, Mms1. Although the Rtt101(Mms1/Mms22) ubiquitin ligase is important in promoting replication through damaged templates, how it does so has yet to be determined. Here we show that mms1Δ and mms22Δ cells fail to properly regulate DNA replication fork progression when replication stress is present and are defective in recovery from replication fork stress. Consistent with a role in promoting DNA replication, we find that Mms1 is enriched at sites where replication forks have stalled and that this localization requires the known binding partners of Mms1-Rtt101 and Mms22. Mms1 and Mms22 stabilize the replisome during replication stress, as binding of the fork-pausing complex components Mrc1 and Csm3, and DNA polymerase ε, at stalled replication forks is decreased in mms1Δ and mms22Δ. Taken together, these data indicate that Mms1 and Mms22 are important for maintaining the integrity of the replisome when DNA replication forks are slowed by hydroxyurea and thereby promote efficient recovery from replication stress.
authors: Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors: Jessica A
authors: JA
authors: Vaisica
authors: Anastasija
authors: A
authors: Baryshnikova
authors: Michael
authors: M
authors: Costanzo
authors: Charles
authors: C
authors: Boone
authors: Grant W
authors: GW
authors: Brown
references: J Mol Biol. 2005 Apr 1;347(3):509-21
references: 15755447
references: Genetics. 2007 Sep;177(1):47-61
references: 17660542
references: Genes Cells. 2003 May;8(5):465-80
references: 12694535
references: Science. 2002 Jul 26;297(5581):599-602
references: 12142537
references: DNA Repair (Amst). 2008 May 3;7(5):811-8
references: 18321796
references: EMBO J. 2009 Apr 22;28(8):1142-56
references: 19279665
references: Science. 2007 Mar 9;315(5817):1411-5
references: 17347440
references: Genes Dev. 2009 Apr 15;23(8):963-74
references: 19390089
references: EMBO J. 2000 May 2;19(9):2082-93
references: 10790374
references: Genes Dev. 2003 Jul 15;17(14):1755-67
references: 12865299
references: Science. 2010 Jan 22;327(5964):425-31
references: 20093466
references: Mol Cell. 2003 May;11(5):1323-36
references: 12769855
references: Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12765-70
references: 19515819
references: Nat Cell Biol. 2006 Apr;8(4):358-66
references: 16531994
references: Mol Cell. 2006 May 5;22(3):383-94
references: 16678110
references: DNA Repair (Amst). 2007 Jun 1;6(6):770-80
references: 17307401
references: Genome Res. 2007 Dec;17(12):1774-82
references: 17989249
references: J Biol Chem. 2010 Mar 26;285(13):9858-9867
references: 20139071
references: Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2588-93
references: 16473935
references: Nature. 2003 Aug 28;424(6952):1078-83
references: 12944972
references: Mol Cell. 2008 Apr 25;30(2):137-44
references: 18439893
references: Mol Cell Biol. 2004 Oct;24(19):8342-55
references: 15367656
references: Mol Cell. 2008 Oct 10;32(1):106-17
references: 18851837
references: Oncogene. 2004 Feb 12;23(6):1206-13
references: 14647447
references: Mol Cell Biol. 2007 Sep;27(18):6396-406
references: 17636020
references: Mol Cell. 2004 Oct 22;16(2):173-85
references: 15494305
references: Methods Enzymol. 2006;409:389-410
references: 16793414
references: DNA Repair (Amst). 2009 Dec 3;8(12):1390-9
references: 19819763
references: Mol Genet Genomics. 2002 Jan;266(5):848-57
references: 11810260
references: Cell. 2005 May 6;121(3):387-400
references: 15882621
references: PLoS Genet. 2010 Feb 19;6(2):e1000852
references: 20174551
references: Genes Dev. 2005 Aug 15;19(16):1905-19
references: 16103218
references: EMBO J. 2009 Dec 2;28(23):3693-705
references: 19910927
references: Mol Cell. 2006 Sep 15;23(6):787-99
references: 16962805
references: EMBO J. 2003 Aug 15;22(16):4325-36
references: 12912929
references: Nat Methods. 2010 Dec;7(12):1017-24
references: 21076421
references: EMBO J. 2009 Oct 7;28(19):2992-3004
references: 19661920
references: Nucleic Acids Res. 2005 Feb 17;33(3):1021-30
references: 15718301
references: Cell. 2006 Mar 10;124(5):1069-81
references: 16487579
references: Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16934-9
references: 12482937
references: Mol Cell Biol. 2000 May;20(9):3086-96
references: 10757793
references: Cell. 1997 Oct 3;91(1):59-69
references: 9335335
references: Genes Dev. 1998 Sep 15;12(18):2956-70
references: 9744871
references: Genes Dev. 2003 May 1;17(9):1153-65
references: 12730134
references: Nat Cell Biol. 2006 Feb;8(2):148-55
references: 16429127
references: Nature. 2002 Jan 10;415(6868):180-3
references: 11805837
references: Nucleic Acids Res. 2010 Jan;38(Database issue):D502-7
references: 19880385
references: Genes Dev. 1994 Mar 15;8(6):652-65
references: 7926756
references: Methods Enzymol. 1991;194:3-21
references: 2005794
references: Genes Dev. 2005 Dec 15;19(24):3055-69
references: 16357221
references: Trends Biochem Sci. 2009 Nov;34(11):562-70
references: 19818632
references: Mol Cell. 2005 Sep 2;19(5):699-706
references: 16137625
references: Science. 2007 Jul 6;317(5834):127-30
references: 17615360
references: Cancer Res. 2009 Mar 15;69(6):2630-7
references: 19276361
references: Nat Cell Biol. 2003 Nov;5(11):1008-15
references: 14578910
references: Curr Biol. 2006 Apr 18;16(8):786-92
references: 16631586
references: J Biol Chem. 2003 Jun 20;278(25):22828-37
references: 12676951
references: Mol Cell. 2005 Sep 2;19(5):691-7
references: 16137624
references: J Bacteriol. 1973 Jan;113(1):263-70
references: 4120066
references: EMBO Rep. 2008 Oct;9(10):1034-40
references: 18704118
references: Mol Biol Cell. 2008 Jan;19(1):171-80
references: 17978089
references: EMBO J. 2005 Jan 26;24(2):405-17
references: 15616582
references: Nat Genet. 2001 Dec;29(4):426-34
references: 11726929
references: Yeast. 1998 Jan 30;14(2):115-32
references: 9483801
references: Cancer Res. 1968 Aug;28(8):1559-65
references: 4876978
references: J Biol Chem. 1984 Jun 25;259(12):7936-40
references: 6376495
references: Genes Cells. 2005 Apr;10(4):297-309
references: 15773893
references: Nat Cell Biol. 2001 Nov;3(11):958-65
references: 11715016
references: Mol Biol Cell. 2006 Jan;17(1):539-48
references: 16267268
references: Nat Struct Mol Biol. 2010 Nov;17(11):1391-7
references: 20972444
references: Nature. 2001 Aug 2;412(6846):557-61
references: 11484058
references: Mol Cell Biol. 2008 Sep;28(17):5359-68
references: 18591249
references: Genes Cells. 2009 Jun;14(6):669-82
references: 19422421
references: Nature. 2007 Apr 12;446(7137):806-10
references: 17314980
references: J Biol Chem. 2009 Dec 4;284(49):34355-65
references: 19819872
references: Genes Cells. 2009 Jul;14(7):807-20
references: 19496828
references: J Biol Chem. 1984 Jun 25;259(12):7532-9
references: 6376490