title: HOXD13 binds DNA replication origins to promote origin licensing and is inhibited by geminin.
abstract: HOX DNA-binding proteins control patterning during development by regulating processes such as cell aggregation and proliferation. Recently, a possible involvement of HOX proteins in replication origin activity was suggested by results showing that a number of HOX proteins interact with the DNA replication licensing regulator geminin and bind a characterized human origin of replication. The functional significance of these observations, however, remained unclear. We show that HOXD13, HOXD11, and HOXA13 bind in vivo all characterized human replication origins tested. We furthermore show that HOXD13 interacts with the CDC6 loading factor, promotes pre-replication complex (pre-RC) proteins assembly at origins, and stimulates DNA synthesis in an in vivo replication assay. HOXD13 expression in cultured cells accelerates DNA synthesis initiation in correlation with the earlier pre-RC recruitment onto origins during G(1) phase. Geminin, which interacts with HOXD13 as well, blocks HOXD13-mediated assembly of pre-RC proteins and inhibits HOXD13-induced DNA replication. Our results uncover a function for Hox proteins in the regulation of replication origin activity and reveal an unforeseen role for the inhibition of HOX protein activity by geminin in the context of replication origin licensing.
authors.affiliation: Department of Animal Biology, University of Modena and Reggio Emilia, Via G. Campi 213/d, Modena 41100, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Salsi
authors.forename: Silvia
authors.initials: S
authors.lastname: Ferrari
authors.forename: Roberta
authors.initials: R
authors.lastname: Ferraresi
authors.forename: Andrea
authors.initials: A
authors.lastname: Cossarizza
authors.forename: Alexis
authors.initials: A
authors.lastname: Grande
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Zappavigna
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication; D016193:G1 Phase; D064248:Geminin; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D018741:Replication Origin / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; C577995:GMNN protein, human; D064248:Geminin; C513184:HOXD13 protein, human; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D004247:DNA
references.citation: Exp Physiol. 1990 May;75(3):309-19
references.pmid: 2161676
references.citation: J Biol Chem. 2006 Jan 27;281(4):1992-9
references.pmid: 16314414
references.citation: Cell Mol Life Sci. 2005 Jul;62(13):1425-33
references.pmid: 15870955
references.citation: Dev Biol. 2008 May 15;317(2):497-507
references.pmid: 18407260
references.citation: Genes Dev. 2005 Jul 15;19(14):1723-34
references.pmid: 16024661
references.citation: Genes Dev. 1994 Mar 15;8(6):732-44
references.pmid: 7926763
references.citation: Cell. 1994 Jul 29;78(2):191-201
references.pmid: 7913880
references.citation: Development. 1996 Apr;122(4):1175-85
references.pmid: 8620844
references.citation: EMBO J. 1999 Oct 15;18(20):5683-90
references.pmid: 10523311
references.citation: Mol Biol Cell. 1999 Aug;10(8):2631-45
references.pmid: 10436018
references.citation: Virology. 2003 Oct 10;315(1):103-9
references.pmid: 14592763
references.citation: Nature. 2007 Jul 26;448(7152):445-51
references.pmid: 17597761
references.citation: Nat Protoc. 2007;2(11):2719-27
references.pmid: 18007607
references.citation: Exp Cell Res. 1999 Apr 10;248(1):1-9
references.pmid: 10094807
references.citation: Mol Cell Biol. 1998 Nov;18(11):6679-97
references.pmid: 9774682
references.citation: Cell Tissue Res. 1999 Apr;296(1):19-25
references.pmid: 10199961
references.citation: EMBO J. 1998 Dec 15;17(24):7219-29
references.pmid: 9857179
references.citation: Development. 2003 Jul;130(14):3095-109
references.pmid: 12783783
references.citation: Bioessays. 2005 Nov;27(11):1107-16
references.pmid: 16237674
references.citation: Mol Cell Biol. 1999 Jan;19(1):547-55
references.pmid: 9858578
references.citation: Cancer Res. 2003 Nov 1;63(21):7356-64
references.pmid: 14612534
references.citation: Dev Biol. 2005 Mar 15;279(2):462-80
references.pmid: 15733672
references.citation: Mol Hum Reprod. 1997 Feb;3(2):115-31
references.pmid: 9239717
references.citation: Cell. 1993 Nov 5;75(3):431-41
references.pmid: 8106170
references.citation: EMBO J. 2003 Jan 2;22(1):89-99
references.pmid: 12505987
references.citation: J Mol Biol. 2000 Jun 9;299(3):667-80
references.pmid: 10835276
references.citation: Stem Cells. 2005 Apr;23(4):496-506
references.pmid: 15790771
references.citation: EMBO J. 2003 Jul 15;22(14):3715-24
references.pmid: 12853486
references.citation: Science. 2000 Dec 22;290(5500):2309-12
references.pmid: 11125146
references.citation: Biochem Biophys Res Commun. 1998 May 29;246(3):771-6
references.pmid: 9618287
references.citation: Mol Cell Biol. 2002 Feb;22(4):1036-48
references.pmid: 11809796
references.citation: Cell Cycle. 2009 Feb 1;8(3):454-9
references.pmid: 19182517
references.citation: Oncogene. 2004 Jan 8;23(1):58-70
references.pmid: 14712211
references.citation: Blood. 1999 May 15;93(10):3276-85
references.pmid: 10233879
references.citation: Genes Cells. 2002 Jun;7(6):523-34
references.pmid: 12059957
references.citation: J Mol Biol. 1967 Jun 14;26(2):365-9
references.pmid: 4291934
references.citation: Cell. 1998 Jun 12;93(6):1043-53
references.pmid: 9635433
references.citation: Osteoarthritis Cartilage. 2003 Apr;11(4):233-41
references.pmid: 12681949
references.citation: Curr Opin Genet Dev. 1995 Aug;5(4):525-8
references.pmid: 7580146
references.citation: Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):5799-803
references.pmid: 1321423
references.citation: Mech Dev. 2002 Mar;112(1-2):219-32
references.pmid: 11850199
references.citation: Science. 1995 Nov 10;270(5238):994-7
references.pmid: 7481806
references.citation: Nature. 2004 Feb 19;427(6976):749-53
references.pmid: 14973489
references.citation: Development. 2004 Sep;131(18):4581-92
references.pmid: 15342482
references.citation: Genes Dev. 2005 Dec 1;19(23):2827-36
references.pmid: 16322558
references.citation: Development. 2005 Jul;132(13):3055-67
references.pmid: 15944189
references.citation: Semin Cell Dev Biol. 2005 Jun;16(3):343-53
references.pmid: 15840443
references.citation: Hum Gene Ther. 1996 Aug 1;7(12):1405-13
references.pmid: 8844199
references.citation: Oncogene. 2002 Sep 26;21(43):6624-32
references.pmid: 12242660
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2420-4
references.pmid: 15699330
references.citation: Development. 2006 Jun;133(11):2263-73
references.pmid: 16672333
references.citation: Curr Opin Genet Dev. 1997 Aug;7(4):481-7
references.pmid: 9309178
references.citation: Exp Mol Pathol. 2007 Apr;82(2):190-6
references.pmid: 17196195
references.citation: Free Radic Res. 2005 Nov;39(11):1249-58
references.pmid: 16298752
references.citation: Exp Cell Res. 1988 Dec;179(2):565-74
references.pmid: 3056733
references.citation: Bioessays. 2003 Dec;25(12):1158-67
references.pmid: 14635251
references.citation: Nature. 2004 Feb 19;427(6976):745-9
references.pmid: 14973488
references.citation: Nature. 1996 Jan 11;379(6561):180-2
references.pmid: 8538771
references.citation: EMBO Rep. 2006 Apr;7(4):425-30
references.pmid: 16439999
references.citation: Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7119-23
references.pmid: 8041756
references.citation: J Biol Chem. 2002 Aug 30;277(35):31430-40
references.pmid: 12004060
references.citation: Development. 2003 Apr;130(8):1701-12
references.pmid: 12620993
references.citation: J Biol Chem. 2004 Aug 20;279(34):35879-89
references.pmid: 15190069
references.citation: Ann N Y Acad Sci. 2005 Jun;1044:109-16
references.pmid: 15958703
references.citation: Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8392-6
references.pmid: 7690960
references.citation: Genes Dev. 2000 Sep 15;14(18):2330-43
references.pmid: 10995389