title: Coordination between polymerase beta and FEN1 can modulate CAG repeat expansion.
abstract: The oxidized DNA base 8-oxoguanine (8-oxoG) is implicated in neuronal CAG repeat expansion associated with Huntington disease, yet it is unclear how such a DNA base lesion and its repair might cause the expansion. Here, we discovered size-limited expansion of CAG repeats during repair of 8-oxoG in a wild-type mouse cell extract. This expansion was deficient in extracts from cells lacking pol beta and HMGB1. We demonstrate that expansion is mediated through pol beta multinucleotide gap-filling DNA synthesis during long-patch base excision repair. Unexpectedly, FEN1 promotes expansion by facilitating ligation of hairpins formed by strand slippage. This alternate role of FEN1 and the polymerase beta (pol beta) multinucleotide gap-filling synthesis is the result of uncoupling of the usual coordination between pol beta and FEN1. HMGB1 probably promotes expansion by stimulating APE1 and FEN1 in forming single strand breaks and ligatable nicks, respectively. This is the first report illustrating that disruption of pol beta and FEN1 coordination during long-patch BER results in CAG repeat expansion.
authors.affiliation: Laboratory of Structural Biology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory of Structural Biology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Prasad
authors.affiliation: Laboratory of Structural Biology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors.forename: William A
authors.initials: WA
authors.lastname: Beard
authors.affiliation: Laboratory of Structural Biology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors.forename: Esther W
authors.initials: EW
authors.lastname: Hou
authors.affiliation: Laboratory of Structural Biology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Horton
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, Rochester, Minnesota 55905.
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: McMurray
authors.affiliation: Laboratory of Structural Biology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709. Electronic address: wilson5@niehs.nih.gov.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Wilson
mesh_terms: D000818:Animals; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D045585:Flap Endonucleases / Q000235:genetics / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D019680:Trinucleotide Repeat Expansion
chemical_list: D024243:HMGB1 Protein; C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA; D019951:DNA Polymerase beta; D045585:Flap Endonucleases; C468317:FEN1 protein, human; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human
references.citation: Cell. 1995 May 19;81(4):533-40
references.pmid: 7758107
references.citation: Nat Genet. 2001 Apr;27(4):407-11
references.pmid: 11279522
references.citation: Nucleic Acids Res. 1999 Jan 15;27(2):616-23
references.pmid: 9862988
references.citation: J Biol Chem. 2004 Nov 12;279(46):47411-4
references.pmid: 15326170
references.citation: J Biol Chem. 1998 Jan 9;273(2):898-902
references.pmid: 9422747
references.citation: J Biol Chem. 2002 Nov 1;277(44):41379-89
references.pmid: 12196536
references.citation: Cancer Epidemiol Biomarkers Prev. 2007 Mar;16(3):473-80
references.pmid: 17372242
references.citation: Mol Cell Biol. 2003 May;23(9):3152-62
references.pmid: 12697816
references.citation: Mol Cell. 2004 Jul 23;15(2):209-20
references.pmid: 15260972
references.citation: Hum Mol Genet. 1998 Aug;7(8):1285-91
references.pmid: 9668171
references.citation: J Biol Chem. 2000 Apr 7;275(14):10498-505
references.pmid: 10744741
references.citation: Nature. 2007 Jun 21;447(7147):932-40
references.pmid: 17581576
references.citation: Biochemistry. 1998 Jun 30;37(26):9426-34
references.pmid: 9649325
references.citation: Hum Mol Genet. 2003 Dec 15;12(24):3359-67
references.pmid: 14570710
references.citation: Nat Rev Genet. 2005 Oct;6(10):729-42
references.pmid: 16205713
references.citation: J Biol Chem. 1998 Jun 12;273(24):15263-70
references.pmid: 9614142
references.citation: EMBO J. 1994 Mar 1;13(5):1235-46
references.pmid: 8131753
references.citation: Methods Enzymol. 2006;408:48-64
references.pmid: 16793362
references.citation: J Biol Chem. 1998 Aug 14;273(33):21203-9
references.pmid: 9694877
references.citation: J Biol Chem. 1999 Jun 25;274(26):18341-50
references.pmid: 10373438
references.citation: Mol Cell. 2007 Sep 7;27(5):829-41
references.pmid: 17803946
references.citation: Science. 1992 Aug 28;257(5074):1220-4
references.pmid: 1355616
references.citation: Hum Mol Genet. 1993 Sep;2(9):1397-400
references.pmid: 8242063
references.citation: Nucleic Acids Res. 2005 Jul 08;33(12):3785-98
references.pmid: 16006624
references.citation: J Biol Chem. 2002 Jun 21;277(25):22361-9
references.pmid: 11948189
references.citation: J Biol Chem. 2003 Apr 18;278(16):13728-39
references.pmid: 12554738
references.citation: J Biol Chem. 2000 Jan 21;275(3):2211-8
references.pmid: 10636928
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3467-72
references.pmid: 18299573
references.citation: Int J Biochem Cell Biol. 2007;39(1):44-84
references.pmid: 16978905
references.citation: Nat Genet. 1999 Dec;23(4):471-3
references.pmid: 10581038
references.citation: Proc Natl Acad Sci U S A. 1985 Aug;82(16):5270-4
references.pmid: 2410918
references.citation: Mol Cell. 1999 Dec;4(6):1079-85
references.pmid: 10635332
references.citation: Mol Cell. 2007 Feb 23;25(4):575-86
references.pmid: 17317629
references.citation: J Biol Chem. 2005 Feb 4;280(5):3665-74
references.pmid: 15561706
references.citation: Nat Genet. 2002 May;31(1):37-46
references.pmid: 11967533
references.citation: J Biol Chem. 2000 Feb 11;275(6):4460-6
references.pmid: 10660619
references.citation: J Biol Chem. 2008 May 9;283(19):13341-56
references.pmid: 18263578
references.citation: Mov Disord. 1999 Nov;14(6):972-80
references.pmid: 10584672
references.citation: J Biol Chem. 2004 May 28;279(22):23088-97
references.pmid: 15037629
references.citation: Eur J Cancer. 2006 Nov;42(16):2833-7
references.pmid: 17010601
references.citation: J Biol Chem. 1997 Jan 10;272(2):1302-7
references.pmid: 8995436
references.citation: Science. 1998 Feb 6;279(5352):853-6
references.pmid: 9452383
references.citation: Annu Rev Neurosci. 1996;19:79-107
references.pmid: 8833437
references.citation: J Biol Chem. 1996 Jul 26;271(30):17811-5
references.pmid: 8663612
references.citation: Nature. 2007 May 24;447(7143):447-52
references.pmid: 17450122
references.citation: Chem Rev. 2006 Feb;106(2):361-82
references.pmid: 16464010
references.citation: J Neurochem. 2001 Dec;79(6):1246-9
references.pmid: 11752065
references.citation: J Biol Chem. 1996 Feb 9;271(6):2875-8
references.pmid: 8621672
references.citation: Carcinogenesis. 2009 Jan;30(1):2-10
references.pmid: 18978338
references.citation: Methods Enzymol. 1995;262:98-107
references.pmid: 8594388
references.citation: J Biol Chem. 2000 Jun 2;275(22):16420-7
references.pmid: 10748145
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):1823-5
references.pmid: 10051552
references.citation: EMBO J. 2000 May 15;19(10):2381-90
references.pmid: 10811629
references.citation: Nature. 1996 Jan 11;379(6561):183-6
references.pmid: 8538772
references.citation: EMBO J. 2001 Oct 15;20(20):5791-801
references.pmid: 11598021
references.citation: Mol Cell Biol. 2003 Sep;23(17):6063-74
references.pmid: 12917330
references.citation: Mol Cell Biol. 2001 Aug;21(15):4889-99
references.pmid: 11438646
references.citation: Hum Mol Genet. 2000 Oct 12;9(17):2539-44
references.pmid: 11030759
references.citation: Mol Cell Biol. 2004 May;24(9):4049-64
references.pmid: 15082797
references.citation: Mol Cell Biol. 1999 Aug;19(8):5675-84
references.pmid: 10409756
references.citation: Hum Mol Genet. 2000 Feb 12;9(3):439-45
references.pmid: 10655554
references.citation: Mol Cell Biol. 1994 Sep;14(9):6187-97
references.pmid: 7915006
references.citation: Annu Rev Biochem. 2004;73:589-615
references.pmid: 15189154
references.citation: Mutat Res. 1998 Jun;407(3):203-15
references.pmid: 9653447
references.citation: J Biol Chem. 2005 Nov 25;280(47):39095-103
references.pmid: 16188889
references.citation: Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1504-9
references.pmid: 9990053