title: Crystal structures of RMI1 and RMI2, two OB-fold regulatory subunits of the BLM complex.
abstract: Mutations in BLM, a RecQ-like helicase, are linked to the autosomal recessive cancer-prone disorder Bloom's syndrome. BLM associates with topoisomerase (Topo) IIIα, RMI1, and RMI2 to form the BLM complex that is essential for genome stability. The RMI1-RMI2 heterodimer stimulates the dissolution of double Holliday junction into non-crossover recombinants mediated by BLM-Topo IIIα and is essential for stabilizing the BLM complex. However, the molecular basis of these functions of RMI1 and RMI2 remains unclear. Here we report the crystal structures of multiple domains of RMI1-RMI2, providing direct confirmation of the existence of three oligonucleotide/oligosaccharide binding (OB)-folds in RMI1-RMI2. Our structural and biochemical analyses revealed an unexpected insertion motif in RMI1N-OB, which is important for stimulating the dHJ dissolution. We also revealed the structural basis of the interaction between RMI1C-OB and RMI2-OB and demonstrated the functional importance of the RMI1-RMI2 interaction in genome stability maintenance.
authors.affiliation: Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Yuting
authors.initials: Y
authors.lastname: Yang
authors.forename: Thiyam Ramsing
authors.initials: TR
authors.lastname: Singh
authors.forename: Valeria
authors.initials: V
authors.lastname: Busygina
authors.forename: Rong
authors.initials: R
authors.lastname: Guo
authors.forename: Ke
authors.initials: K
authors.lastname: Wan
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
authors.forename: Patrick
authors.initials: P
authors.lastname: Sung
authors.forename: Amom Ruhikanta
authors.initials: AR
authors.lastname: Meetei
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
mesh_terms: D001816:Bloom Syndrome / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D045566:DNA, Cruciform / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D021122:Protein Subunits
chemical_list: D002352:Carrier Proteins; D045566:DNA, Cruciform; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D021122:Protein Subunits; C501527:RMI1 protein, human; C533196:RMI2 protein, human; D004264:DNA Topoisomerases, Type I
references.citation: EMBO J. 2002 Apr 2;21(7):1855-63
references.pmid: 11927569
references.citation: J Biol Chem. 2005 Apr 8;280(14):13921-7
references.pmid: 15695524
references.citation: Cell. 1998 Dec 23;95(7):963-74
references.pmid: 9875850
references.citation: Structure. 1998 Jan 15;6(1):11-21
references.pmid: 9493263
references.citation: Nature. 2007 Feb 1;445(7127):506-10
references.pmid: 17237768
references.citation: Biochemistry. 1999 Mar 30;38(13):3963-73
references.pmid: 10194308
references.citation: J Biol Chem. 2000 Mar 31;275(13):9636-44
references.pmid: 10734115
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11118-23
references.pmid: 16849422
references.citation: Mol Cell Biol. 2005 Jun;25(11):4476-87
references.pmid: 15899853
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W321-6
references.pmid: 15215403
references.citation: J Biol Chem. 2006 May 19;281(20):13861-4
references.pmid: 16595695
references.citation: Nature. 2003 Nov 13;426(6963):198-203
references.pmid: 14614509
references.citation: Genes Dev. 2008 Oct 15;22(20):2843-55
references.pmid: 18923082
references.citation: Dev Cell. 2010 Feb 16;18(2):214-25
references.pmid: 20159592
references.citation: EMBO J. 2005 Apr 6;24(7):1465-76
references.pmid: 15775963
references.citation: J Mol Biol. 1991 Mar 5;218(1):183-94
references.pmid: 2002501
references.citation: Chromosoma. 2008 Jun;117(3):219-33
references.pmid: 18188578
references.citation: EMBO J. 2003 Jun 2;22(11):2561-70
references.pmid: 12773373
references.citation: Curr Opin Struct Biol. 2004 Feb;14(1):36-42
references.pmid: 15102447
references.citation: Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21
references.pmid: 9757107
references.citation: Science. 1996 Oct 18;274(5286):415-21
references.pmid: 8832889
references.citation: Genes Dev. 2009 Dec 15;23(24):2900-14
references.pmid: 20008938
references.citation: J Biol Chem. 2006 Aug 11;281(32):22839-46
references.pmid: 16766518
references.citation: Methods Enzymol. 1997;276:307-26
references.pmid: 27754618
references.citation: EMBO J. 1999 Aug 16;18(16):4498-504
references.pmid: 10449415
references.citation: Cell. 1995 Nov 17;83(4):655-66
references.pmid: 7585968
references.citation: J Biol Chem. 2008 Jun 6;283(23):15701-8
references.pmid: 18390547
references.citation: Mol Cell. 2000 May;5(5):865-76
references.pmid: 10882122
references.citation: J Biomol NMR. 1999 Aug;14(4):321-31
references.pmid: 10526407
references.citation: J Biol Chem. 2002 Aug 23;277(34):30515-23
references.pmid: 12034743
references.citation: Acta Crystallogr A. 1991 Mar 1;47 ( Pt 2):110-9
references.pmid: 2025413
references.citation: J Mol Biol. 2000 May 5;298(3):407-16
references.pmid: 10772859
references.citation: Nature. 1997 Jan 9;385(6612):176-81
references.pmid: 8990123
references.citation: Nat Struct Mol Biol. 2004 Dec;11(12):1223-9
references.pmid: 15558049
references.citation: J Biol Chem. 2000 Sep 1;275(35):26898-905
references.pmid: 10862619
references.citation: Mol Cell Biol. 2003 May;23(10):3417-26
references.pmid: 12724401
references.citation: EMBO J. 2005 Jun 1;24(11):2024-33
references.pmid: 15889139
references.citation: Methods Enzymol. 1997;276:472-494
references.pmid: 27799110
references.citation: J Biol Chem. 1999 Oct 8;274(41):29075-80
references.pmid: 10506160
references.citation: Nature. 2003 Dec 18;426(6968):870-4
references.pmid: 14685245
references.citation: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2006 Aug 1;62(Pt 8):731-4
references.pmid: 16880543
references.citation: Mol Cell Biol. 1994 Dec;14(12):8391-8
references.pmid: 7969174
references.citation: Genes Dev. 2008 Oct 15;22(20):2856-68
references.pmid: 18923083
references.citation: Mol Cell Biol. 2004 Feb;24(3):1279-91
references.pmid: 14729972
references.citation: Biochemistry. 1999 Mar 30;38(13):3974-84
references.pmid: 10194309
references.citation: J Mol Biol. 2004 Apr 23;338(2):241-55
references.pmid: 15066429
references.citation: J Biol Chem. 2007 Oct 26;282(43):31484-92
references.pmid: 17728255
references.citation: EMBO J. 2000 Nov 15;19(22):6266-74
references.pmid: 11080172
references.citation: Mol Cell Biol. 2008 Dec;28(24):7345-53
references.pmid: 18936170
references.citation: J Biol Chem. 2007 Sep 28;282(39):28971-28979
references.pmid: 17693398