title: Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability.
abstract: XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective XPG mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known about how XPG loss results in this devastating disease. We identify XPG as a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR). XPG depletion causes DNA double-strand breaks, chromosomal abnormalities, cell-cycle delays, defective HRR, inability to overcome replication fork stalling, and replication stress. XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation. Upstream in HRR, XPG interacts directly with BRCA1. Its depletion causes BRCA1 hyper-phosphorylation and persistent chromatin binding. These unexpected findings establish XPG as an HRR protein with important roles in genome stability and suggest how XPG defects produce severe clinical consequences including cancer and accelerated aging.
authors.affiliation: Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Trego
authors.affiliation: Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Torsten
authors.initials: T
authors.lastname: Groesser
authors.affiliation: The Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Albert R
authors.initials: AR
authors.lastname: Davalos
authors.affiliation: Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Parplys
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Weixing
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Nelson
authors.affiliation: Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Ayesu
authors.initials: A
authors.lastname: Hlaing
authors.affiliation: Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Shih
authors.affiliation: Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Björn
authors.initials: B
authors.lastname: Rydberg
authors.affiliation: Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Janice M
authors.initials: JM
authors.lastname: Pluth
authors.affiliation: Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Miaw-Sheue
authors.initials: MS
authors.lastname: Tsai
authors.affiliation: Department of Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
authors.forename: Jan H J
authors.initials: JHJ
authors.lastname: Hoeijmakers
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sung
authors.affiliation: Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wiese
authors.affiliation: Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; The Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
authors.affiliation: Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Electronic address: pkcooper@lbl.gov.
authors.forename: Priscilla K
authors.initials: PK
authors.lastname: Cooper
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism*; D024682:BRCA2 Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D003057:Cockayne Syndrome / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics* / Q000378:metabolism; D000076164:Fanconi Anemia Complementation Group N Protein; D015894:Genome, Human; D042822:Genomic Instability; D006367:HeLa Cells; D059765:Homologous Recombination; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D051135:Rad51 Recombinase / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004268:DNA-Binding Proteins; D004720:Endonucleases; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; D051135:Rad51 Recombinase; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000099250:DNA Excision Repair Protein ERCC-5; C492913:BRCA1 protein, human; C551750:BRCA2 protein, human; C512790:PALB2 protein, human; C495153:RAD51 protein, human
references.citation: Mol Cell. 2007 Nov 9;28(3):482-90
references.pmid: 17996711
references.citation: Radiat Res. 2007 Dec;168(6):675-82
references.pmid: 18088180
references.citation: Cell Res. 2008 Jan;18(1):73-84
references.pmid: 18166977
references.citation: DNA Repair (Amst). 2008 Feb 1;7(2):339-44
references.pmid: 18077223
references.citation: Annu Rev Biochem. 2008;77:229-57
references.pmid: 18275380
references.citation: DNA Repair (Amst). 2009 Apr 5;8(4):544-56
references.pmid: 19213613
references.citation: EMBO J. 2009 Apr 22;28(8):1111-20
references.pmid: 19279666
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7155-60
references.pmid: 19369211
references.citation: Nat Struct Mol Biol. 2009 Jun;16(6):589-97
references.pmid: 19491936
references.citation: Nat Struct Mol Biol. 2010 Oct;17(10):1263-5
references.pmid: 20729858
references.citation: Nat Struct Mol Biol. 2010 Oct;17(10):1260-2
references.pmid: 20729859
references.citation: Nat Struct Mol Biol. 2010 Oct;17(10):1247-54
references.pmid: 20871615
references.citation: Nat Struct Mol Biol. 2010 Oct;17(10):1255-9
references.pmid: 20871616
references.citation: Nature. 2010 Oct 7;467(7316):678-83
references.pmid: 20729832
references.citation: Mutat Res. 2010 Dec 10;694(1-2):60-4
references.pmid: 20817001
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):686-91
references.pmid: 21148102
references.citation: J Biol Chem. 2011 Apr 15;286(15):13669-80
references.pmid: 21335604
references.citation: Cell. 2011 May 13;145(4):529-42
references.pmid: 21565612
references.citation: Cell Cycle. 2011 Jun 15;10(12):1998-2007
references.pmid: 21558802
references.citation: DNA Repair (Amst). 2011 Jul 15;10(7):722-9
references.pmid: 21592868
references.citation: Nat Rev Cancer. 2012 Jan;12(1):68-78
references.pmid: 22193408
references.citation: Mol Cell. 2012 Mar 30;45(6):710-8
references.pmid: 22464441
references.citation: Cancer Cell. 2012 Jul 10;22(1):106-16
references.pmid: 22789542
references.citation: Methods Mol Biol. 2012;920:379-91
references.pmid: 22941618
references.citation: Mol Cell Biol. 2013 Jan;33(2):387-95
references.pmid: 23149936
references.citation: Mol Cell. 2013 Mar 7;49(5):872-83
references.pmid: 23333306
references.citation: Nat Struct Mol Biol. 2013 Apr;20(4):412-8
references.pmid: 23552296
references.citation: Oncogene. 2013 Jul 25;32(30):3552-8
references.pmid: 22964643
references.citation: Cold Spring Harb Perspect Biol. 2013 Aug;5(8):a012625
references.pmid: 23906714
references.citation: Nat Cell Biol. 2014 Jan;16(1):2-9
references.pmid: 24366029
references.citation: Nat Rev Mol Cell Biol. 2014 Jul;15(7):465-81
references.pmid: 24954209
references.citation: PLoS Genet. 2014 Oct;10(10):e1004686
references.pmid: 25299392
references.citation: Cell Rep. 2014 Nov 20;9(4):1387-401
references.pmid: 25456133
references.citation: DNA Repair (Amst). 2014 Dec;24:87-97
references.pmid: 25288561
references.citation: Mol Cell. 2014 Dec 18;56(6):777-85
references.pmid: 25435140
references.citation: J Cell Biol. 2015 Mar 2;208(5):545-62
references.pmid: 25733713
references.citation: J Cell Biol. 2015 Mar 2;208(5):563-79
references.pmid: 25733714
references.citation: Cold Spring Harb Perspect Biol. 2015 Apr;7(4):a016600
references.pmid: 25833843
references.citation: EMBO J. 2015 May 12;34(10):1399-416
references.pmid: 25820262
references.citation: Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):E3495-504
references.pmid: 26100862
references.citation: Genes Dev. 1999 Oct 15;13(20):2633-8
references.pmid: 10541549
references.citation: Science. 1999 Nov 5;286(5442):1162-6
references.pmid: 10550055
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13300-5
references.pmid: 10557315
references.citation: Genes Dev. 2000 Dec 1;14(23):2989-3002
references.pmid: 11114888
references.citation: Cancer Res. 2001 Jun 15;61(12):4842-50
references.pmid: 11406561
references.citation: Prog Nucleic Acid Res Mol Biol. 2001;68:139-49
references.pmid: 11554293
references.citation: Eur J Paediatr Neurol. 2001;5(6):225-42
references.pmid: 11764181
references.citation: J Invest Dermatol. 2002 Jun;118(6):972-82
references.pmid: 12060391
references.citation: Mol Cell Biol. 2004 Mar;24(6):2237-42
references.pmid: 14993263
references.citation: Mol Cell Biol. 2004 May;24(9):3712-9
references.pmid: 15082767
references.citation: DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1015-24
references.pmid: 15279788
references.citation: Mol Cell Biol. 2004 Nov;24(21):9305-16
references.pmid: 15485900
references.citation: Nature. 1993 May 13;363(6425):185-8
references.pmid: 8483505
references.citation: Nature. 1995 Apr 6;374(6522):566-9
references.pmid: 7700386
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3116-21
references.pmid: 9096355
references.citation: EMBO J. 1998 Jan 15;17(2):598-608
references.pmid: 9430650
references.citation: Mutat Res. 1997 Nov;385(2):107-14
references.pmid: 9447232
references.citation: Exp Cell Res. 1998 Aug 25;243(1):22-8
references.pmid: 9716445
references.citation: Mol Cell Biol. 1999 Mar;19(3):2366-72
references.pmid: 10022922
references.citation: Mol Cell. 2005 Oct 28;20(2):187-98
references.pmid: 16246722
references.citation: Mol Cell. 2006 Jun 23;22(6):719-29
references.pmid: 16793542
references.citation: Cancer Res. 2006 Aug 15;66(16):8109-15
references.pmid: 16912188
references.citation: Nucleic Acids Res. 2006;34(22):6530-9
references.pmid: 17130154
references.citation: Mol Cell. 2007 Apr 27;26(2):231-43
references.pmid: 17466625
references.citation: Mol Cell. 2015 Jul 16;59(2):176-87
references.pmid: 26145171
references.citation: Mol Cell. 2015 Sep 3;59(5):867-81
references.pmid: 26051181
references.citation: Mol Cell. 2015 Oct 15;60(2):280-93
references.pmid: 26474068
references.citation: Nucleic Acids Res. 2015 Nov 16;43(20):9817-34
references.pmid: 26323318
references.citation: Semin Cell Dev Biol. 2014 Jun;30:154-64
references.pmid: 24818779