title: Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons.
abstract: Defects in DNA repair have been extensively linked to neurodegenerative diseases, but the exact mechanisms remain poorly understood. We found that FUS, an RNA/DNA-binding protein that has been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, is important for the DNA damage response (DDR). The function of FUS in DDR involved a direct interaction with histone deacetylase 1 (HDAC1), and the recruitment of FUS to double-stranded break sites was important for proper DDR signaling. Notably, FUS proteins carrying familial ALS mutations were defective in DDR and DNA repair and showed a diminished interaction with HDAC1. Moreover, we observed increased DNA damage in human ALS patients harboring FUS mutations. Our findings suggest that an impaired DDR and DNA repair may contribute to the pathogenesis of neurodegenerative diseases linked to FUS mutations.
authors.affiliation: 1] Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. [3].
authors.forename: Wen-Yuan
authors.initials: WY
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Pan
authors.forename: Susan C
authors.initials: SC
authors.lastname: Su
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Quinn
authors.forename: Megumi
authors.initials: M
authors.lastname: Sasaki
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Jimenez
authors.forename: Ian R A
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000502:physiology; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*
chemical_list: D034702:RNA-Binding Protein FUS; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
references.citation: Nat Genet. 2006 May;38(5):515-7
references.pmid: 16604074
references.citation: Nat Struct Mol Biol. 2010 Sep;17(9):1144-51
references.pmid: 20802485
references.citation: J Med Genet. 2012 Apr;49(4):258-63
references.pmid: 22499346
references.citation: Science. 2002 Feb 1;295(5556):868-72
references.pmid: 11786607
references.citation: Genes Dev. 1999 Oct 15;13(20):2633-8
references.pmid: 10541549
references.citation: J Biol Chem. 2003 Sep 26;278(39):37782-9
references.pmid: 12857758
references.citation: Mol Biotechnol. 2004 Mar;26(3):249-61
references.pmid: 15004294
references.citation: Nature. 2008 Jul 3;454(7200):126-30
references.pmid: 18509338
references.citation: Nature. 2004 Jun 24;429(6994):883-91
references.pmid: 15190254
references.citation: Mol Cell. 1998 Feb;1(3):347-57
references.pmid: 9660919
references.citation: Neuron. 2008 Dec 10;60(5):803-17
references.pmid: 19081376
references.citation: Science. 2009 Feb 27;323(5918):1208-1211
references.pmid: 19251628
references.citation: J Neurochem. 1997 Nov;69(5):2064-74
references.pmid: 9349552
references.citation: Nat Rev Neurosci. 2009 Feb;10(2):100-12
references.pmid: 19145234
references.citation: Methods Enzymol. 2006;409:524-40
references.pmid: 16793422
references.citation: Proc Natl Acad Sci U S A. 2004 May 18;101(20):7624-9
references.pmid: 15123826
references.citation: Nature. 1993 Jun 17;363(6430):640-4
references.pmid: 8510758
references.citation: J Biol Chem. 1999 Nov 26;274(48):34337-42
references.pmid: 10567410
references.citation: Nature. 2010 Aug 26;466(7310):1105-9
references.pmid: 20622856
references.citation: Science. 2002 May 3;296(5569):922-7
references.pmid: 11934988
references.citation: J Mol Cell Biol. 2009 Dec;1(2):82-92
references.pmid: 19783543
references.citation: Science. 2009 Feb 27;323(5918):1205-8
references.pmid: 19251627
references.citation: Genes Dev. 1996 Oct 1;10(19):2411-22
references.pmid: 8843194
references.citation: Biochem Cell Biol. 2006 Aug;84(4):568-77
references.pmid: 16936829
references.citation: Methods Mol Biol. 2009;523:125-40
references.pmid: 19381917
references.citation: Nat Cell Biol. 2011 Oct 03;13(10):1161-9
references.pmid: 21968989
references.citation: Nat Cell Biol. 2009 Oct;11(10):1261-7
references.pmid: 19734887
references.citation: Nature. 2009 May 7;459(7243):55-60
references.pmid: 19424149
references.citation: Eur J Cancer. 1998 Sep;34(10):1514-21
references.pmid: 9893622
references.citation: Nature. 2012 Feb 29;483(7388):222-6
references.pmid: 22388814
references.citation: J Cell Sci. 2005 Dec 15;118(Pt 24):5755-65
references.pmid: 16317045
references.citation: Mol Cell Biol. 2001 Mar;21(5):1719-29
references.pmid: 11238909
references.citation: Cell. 2007 Sep 21;130(6):991-1004
references.pmid: 17889645
references.citation: Brain Res Bull. 2007 Jun 15;73(1-3):48-54
references.pmid: 17499636
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6630-3
references.pmid: 10823907
references.citation: Science. 2008 Jun 13;320(5882):1507-10
references.pmid: 18483401
references.citation: Curr Biol. 2005 Mar 29;15(6):587-93
references.pmid: 15797031
references.citation: Nat Neurosci. 2013 Aug;16(8):1008-15
references.pmid: 23852118
references.citation: J Neurosci. 1996 Mar 1;16(5):1710-9
references.pmid: 8774439
references.citation: Oncogene. 1999 Aug 5;18(31):4515-21
references.pmid: 10442642
references.citation: Brain Pathol. 2010 Nov;20(6):1069-76
references.pmid: 20579074
references.citation: Nat Genet. 2000 Feb;24(2):175-9
references.pmid: 10655065
references.citation: EMBO J. 2000 Feb 1;19(3):453-62
references.pmid: 10654943
references.citation: Acta Neuropathol. 2010 Oct;120(4):461-75
references.pmid: 20602234
references.citation: Nat Neurosci. 2007 Aug;10(8):1063-72
references.pmid: 17603477
references.citation: J Biol Chem. 2002 Jun 7;277(23):20185-94
references.pmid: 11923292
references.citation: Epigenetics Chromatin. 2008 Nov 12;1(1):9
references.pmid: 19014481
references.citation: Genome Biol. 2006;7(10):R100
references.pmid: 17076895
references.citation: Biochem Cell Biol. 2003 Jun;81(3):123-9
references.pmid: 12897845
references.citation: Biochem J. 2008 Oct 15;415(2):297-307
references.pmid: 18620545