title: Role of p97/VCP (Cdc48) in genome stability.
abstract: Ubiquitin-dependent molecular chaperone p97, also known as valosin-containing protein (VCP) or Cdc48, is an AAA ATPase involved in protein turnover and degradation. p97 converts its own ATPase hydrolysis into remodeling activity on a myriad of ubiquitinated substrates from different cellular locations and pathways. In this way, p97 mediates extraction of targeted protein from cellular compartments or protein complexes. p97-dependent protein extraction from various cellular environments maintains cellular protein homeostasis. In recent years, p97-dependent protein extraction from chromatin has emerged as an essential evolutionarily conserved process for maintaining genome stability. Inactivation of p97 segregase activity leads to accumulation of ubiquitinated substrates on chromatin, consequently leading to protein-induced chromatin stress (PICHROS). PICHROS directly and negatively affects multiple DNA metabolic processes, including replication, damage responses, mitosis, and transcription, leading to genotoxic stress and genome instability. By summarizing and critically evaluating recent data on p97 function in various chromatin-associated protein degradation processes, we propose establishing p97 as a genome caretaker.
authors: Institute of Pharmacology and Toxicology, University Zürich-Vetsuisse Zürich, Switzerland ; Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford Oxford, UK.
authors: Bruno
authors: B
authors: Vaz
authors: Swagata
authors: S
authors: Halder
authors: Kristijan
authors: K
authors: Ramadan
keywords: Cdc48; DNA damage response; DNA repair; DNA replication; chromatin-associated protein degradation; genome stability; p97/VCP; protein-induced chromatin stress
references: Nat Cell Biol. 2011 Aug 07;13(9):1116-23
references: 21822278
references: Cell Cycle. 2012 Sep 15;11(18):3395-402
references: 22894931
references: Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5613-7
references: 8516308
references: Mol Biol Cell. 2003 Oct;14(10):4221-9
references: 12937274
references: Structure. 2011 Jun 8;19(6):833-43
references: 21645854
references: Biochim Biophys Acta. 2012 Jan;1823(1):125-9
references: 21963883
references: DNA Repair (Amst). 2010 Dec 10;9(12):1229-40
references: 21056014
references: Genetics. 1982 Apr;100(4):547-63
references: 6749598
references: DNA Repair (Amst). 2009 Sep 2;8(9):1038-46
references: 19482564
references: Elife. 2013 Jan 22;2:e00308
references: 23358411
references: Nat Struct Mol Biol. 2011 Nov 27;18(12):1345-50
references: 22120668
references: Annu Rev Genet. 2002;36:617-56
references: 12429704
references: Genes Cancer. 2010 Sep 2;1(7):753-763
references: 21103003
references: J Cell Sci. 2010 Jun 15;123(Pt 12):2025-34
references: 20483956
references: Mol Cell. 2011 Jan 7;41(1):82-92
references: 21211725
references: Trends Biochem Sci. 2007 Jan;32(1):6-11
references: 17142044
references: Trends Cell Biol. 2012 Sep;22(9):483-91
references: 22818974
references: Mol Cell. 2011 Oct 7;44(1):85-96
references: 21981920
references: Nat Rev Cancer. 2009 Mar;9(3):153-66
references: 19238148
references: Int J Oncol. 2003 Oct;23(4):1015-23
references: 12963981
references: Biochim Biophys Acta. 2008 Dec;1782(12):744-8
references: 18845250
references: Cell Cycle. 2009 Jan 15;8(2):185-90
references: 19158489
references: J Bone Miner Res. 2006 Dec;21 Suppl 2:P58-63
references: 17229010
references: Hum Mol Genet. 2010 Apr 15;19(R1):R38-45
references: 20410287
references: Mol Cell Biol. 2007 Jul;27(13):4617-25
references: 17452455
references: J Cell Biol. 2003 Oct 13;163(1):21-6
references: 14557244
references: Nucleic Acids Res. 2012 Nov;40(21):10795-808
references: 22987070
references: Nat Struct Mol Biol. 2012 Nov;19(11):1093-100
references: 23042607
references: Nat Struct Biol. 2002 Dec;9(12):950-7
references: 12434150
references: Nat Rev Mol Cell Biol. 2012 Feb 23;13(3):141-52
references: 22358330
references: Cancer Res. 2005 Sep 1;65(17):7533-40
references: 16140914
references: Nat Rev Mol Cell Biol. 2005 Dec;6(12):943-53
references: 16341080
references: Nat Cell Biol. 2011 Oct 23;13(11):1376-82
references: 22020440
references: Cell Res. 2008 Jan;18(1):73-84
references: 18166977
references: J Cell Sci. 2011 May 1;124(Pt 9):1571-80
references: 21486945
references: Ann Surg Oncol. 2004 Jul;11(7):697-704
references: 15231524
references: Ann Oncol. 2004 Sep;15(9):1432-8
references: 15319251
references: Mol Cell Biol. 2007 Apr;27(8):3211-6
references: 17296727
references: Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3420-5
references: 19223589
references: Trends Biochem Sci. 2011 Oct;36(10):515-23
references: 21741246
references: J Mol Med (Berl). 2011 Jun;89(6):577-93
references: 21318260
references: FEBS Lett. 2011 Sep 16;585(18):2772-9
references: 21704031
references: J Biol Chem. 2008 Nov 14;283(46):31608-16
references: 18757370
references: Nature. 2009 Mar 26;458(7237):461-7
references: 19325626
references: Nat Cell Biol. 2012 Feb 02;14(2):117-23
references: 22298039
references: J Cell Sci. 2003 Nov 1;116(Pt 21):4283-90
references: 14514884
references: Nat Rev Mol Cell Biol. 2010 Jul;11(7):479-89
references: 20551964
references: Autophagy. 2010 Feb;6(2):217-27
references: 20104022
references: J Struct Biol. 2012 Aug;179(2):104-11
references: 22735043
references: FEBS Lett. 2011 Sep 16;585(18):2914-9
references: 21664912
references: BMC Cancer. 2005 Jul 09;5:77
references: 16004614
references: Nat Rev Genet. 2013 Jan;14(1):62-75
references: 23247436
references: J Struct Biol. 2004 Apr-May;146(1-2):251-9
references: 15037256
references: J Biol Chem. 1995 Jul 21;270(29):17442-56
references: 7615550
references: Nat Rev Cancer. 2012 Dec;12(12):801-17
references: 23175119
references: PLoS One. 2011 Apr 19;6(4):e18988
references: 21526151
references: Biochem Soc Trans. 2007 Nov;35(Pt 5):1334-7
references: 17956345
references: Nat Cell Biol. 2007 Apr;9(4):379-90
references: 17369820
references: Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):12879-84
references: 18728180
references: Mol Cell Biol. 2008 Jul;28(13):4261-74
references: 18458060
references: Genes Dev. 2012 Jun 1;26(11):1196-208
references: 22661230
references: Neuron. 2010 Dec 9;68(5):857-64
references: 21145000
references: Nat Rev Mol Cell Biol. 2012 Dec;13(12):789-803
references: 23175282
references: Autophagy. 2010 Feb;6(2):283-5
references: 20083896
references: Nat Rev Mol Cell Biol. 2010 Mar;11(3):208-19
references: 20177396
references: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12871-6
references: 14566050
references: Cell. 2003 Oct 31;115(3):355-67
references: 14636562
references: EMBO J. 1990 Jun;9(6):1757-67
references: 2140770
references: Nature. 2009 Oct 22;461(7267):1071-8
references: 19847258
references: Nat Struct Mol Biol. 2012 Nov;19(11):1084-92
references: 23042605
references: Mol Cell. 2006 Jun 23;22(6):713-717
references: 16793541
references: Am J Cancer Res. 2011;1(7):845-51
references: 22016832
references: Neuromuscul Disord. 2009 May;19(5):308-15
references: 19380227
references: Cell. 2012 Sep 14;150(6):1182-95
references: 22980979
references: Expert Rev Clin Immunol. 2011 Mar;7(2):169-85
references: 21426255
references: Nat Rev Cancer. 2011 Feb;11(2):96-110
references: 21258395
references: Cell. 2012 Aug 17;150(4):697-709
references: 22884692
references: J Cell Mol Med. 2008 Dec;12(6A):2511-8
references: 18798739
references: FEBS Lett. 2011 Sep 16;585(18):2780-5
references: 21640107
references: J Cell Biol. 2009 Dec 14;187(6):875-88
references: 20008565
references: Nature. 2007 Dec 20;450(7173):1258-62
references: 18097415
references: Nat Rev Cancer. 2011 Aug 24;11(9):629-43
references: 21863050
references: J Biol Chem. 2008 Mar 14;283(11):6817-25
references: 18184650
references: Mol Cell. 2012 Jun 8;46(5):625-35
references: 22681887
references: Nat Struct Mol Biol. 2012 Jan 22;19(2):201-6
references: 22266820
references: EMBO J. 2007 Sep 19;26(18):4089-101
references: 17762865
references: DNA Repair (Amst). 2011 Jul 15;10(7):730-3
references: 21601536
references: Cell Cycle. 2012 Mar 15;11(6):1062-9
references: 22391235
references: J Mol Biol. 2009 Dec 11;394(4):732-46
references: 19782090
references: Nat Cell Biol. 2009 Dec;11(12):1481-6
references: 19915556
references: EMBO J. 2012 Oct 3;31(19):3918-34
references: 22909820
references: Genes Dev. 2012 Jun 1;26(11):1179-95
references: 22661229
references: Clin Cancer Res. 2004 Aug 15;10(16):5558-65
references: 15328197
references: Cell. 2009 Feb 6;136(3):435-46
references: 19203579
references: J Biol Chem. 2012 Aug 24;287(35):29610-9
references: 22730331
references: FEBS Lett. 2011 Sep 16;585(18):2868-75
references: 21536036
references: Mol Cell. 2010 Oct 22;40(2):179-204
references: 20965415
references: Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3737-41
references: 22355145
references: Jpn J Cancer Res. 2002 Mar;93(3):296-304
references: 11927012
references: J Struct Biol. 2006 Oct;156(1):29-40
references: 16529947
references: J Biol Chem. 2012 Oct 5;287(41):34225-33
references: 22902628
references: Nucleic Acids Res. 2013 Feb 1;41(3):1661-8
references: 23254330
references: Cell. 2012 Nov 9;151(4):807-820
references: 23122649
references: Cell. 2008 Sep 5;134(5):804-16
references: 18775313
references: Biochem Soc Trans. 2008 Feb;36(Pt 1):62-7
references: 18208387
references: Mol Cell. 2011 Oct 7;44(1):3-4
references: 21981912
references: Cell. 2009 Feb 6;136(3):420-34
references: 19203578
references: DNA Cell Biol. 2000 May;19(5):253-63
references: 10855792
references: EMBO J. 2012 Apr 18;31(8):1865-78
references: 22373579
references: Clin Cancer Res. 2004 Jan 15;10(2):651-7
references: 14760088
references: Mol Cell. 2011 Oct 7;44(1):72-84
references: 21981919
references: PLoS One. 2011;6(12):e29073
references: 22216170
references: J Clin Oncol. 2003 Jul 1;21(13):2537-44
references: 12829673
references: Mol Biol Cell. 1998 Jan;9(1):131-41
references: 9436996
references: Cell Cycle. 2011 Dec 15;10(24):4300-10
references: 22134242
references: Blood. 2009 Mar 26;113(13):3059-69
references: 18984860
references: J Struct Biol. 2012 Aug;179(2):78-82
references: 22450227