Proteomics insights into DNA damage response and translating this knowledge to clinical strategies.
Genomic instability is a critical driver in the process of cancer formation. At the same time, inducing DNA damage by irradiation or genotoxic compounds constitutes a key therapeutic strategy to kill fast-dividing cancer cells. Sensing of DNA lesions initiates a complex set of signalling pathways, collectively known as the DNA damage response (DDR). Deciphering DDR signalling pathways with high-throughput technologies could provide insights into oncogenic transformation, metastasis formation and therapy responses, and could build a basis for better therapeutic interventions in cancer treatment. Mass spectrometry (MS)-based proteomics emerged as a method of choice for global studies of proteins and their posttranslational modifications (PTMs). MS-based studies of the DDR have aided in delineating DNA damage-induced signalling responses. Those studies identified changes in abundance, interactions and modification of proteins in the context of genotoxic stress. Here we review ground-breaking MS-based proteomics studies, which analysed changes in protein abundance, protein-protein and protein-DNA interactions, phosphorylation, acetylation, ubiquitylation, SUMOylation and Poly(ADP-ribose)ylation (PARylation) in the DDR. Finally, we provide an outlook on how proteomics studies of the DDR could aid clinical developments on multiple levels.
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Louise
L
von Stechow
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Jesper V
JV
Olsen
D004249:DNA Damage; D004260:DNA Repair; D042822:Genomic Instability; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D009369:Neoplasms / Q000235:genetics / Q000628:therapy; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D040901:Proteomics / Q000379:methods*
Biomedicine; Cancer; DNA damage response; DNA-protein interaction; Mass Spectrometry; PTM analysis
Cancer Res. 2015 Apr 1;75(7):1495-503
25670172
Cancer Cell. 2007 Feb;11(2):175-89
17292828
EMBO J. 2016 Jan 4;35(1):6-23
26628622
Science. 2015 May 1;348(6234):1253671
25931565
Curr Opin Cell Biol. 2009 Apr;21(2):245-55
19230643
Drug Discov Today. 2014 Apr;19(4):425-32
24141136
Cell Rep. 2016 Apr 26;15(4):893-908
27149854
Nature. 2012 Jan 18;481(7381):287-94
22258607
Nat Cell Biol. 2012 Oct;14(10):1089-98
23000965
Mol Cell. 2015 Sep 3;59(5):867-81
26051181
Cell. 2015 Oct 22;163(3):712-23
26496610
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19855-60
18077418
Sci Signal. 2010 Jan 12;3(104):ra3
20068231
Nat Rev Mol Cell Biol. 2008 Aug;9(8):616-27
18594563
Cell Rep. 2015 Jun 23;11(11):1834-43
26074081
Nat Methods. 2009 Mar;6(3):203-5
19198594
Methods Enzymol. 2010;470:259-80
20946814
Science. 2007 May 25;316(5828):1160-6
17525332
Nat Methods. 2013 Jan;10(1):24-7
23269373
Mol Cell Proteomics. 2010 Jun;9(6):1314-23
20164059
Oncogene. 2012 May 24;31(21):2601-13
21963855
Mol Cell. 2012 Apr 27;46(2):212-25
22424773
Nature. 2016 May 25;534(7605):55-62
27251275
Mol Cell Proteomics. 2015 May;14(5):1419-34
25755297
DNA Repair (Amst). 2014 Jul;19:214-20
24794401
Nat Rev Genet. 2011 Jan;12(1):56-68
21164525
J Proteome Res. 2012 Nov 2;11(11):5311-22
22985185
Lancet. 2010 Jul 24;376(9737):235-44
20609467
Mol Syst Biol. 2014 Dec 09;10:767
25492886
Cell Rep. 2015 Mar 31;10(12):1947-56
25801034
Cell Cycle. 2007 Sep 15;6(18):2252-7
17700065
Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14973-7
10611322
Cell Res. 2010 Jun;20(6):614-21
20404858
Nat Rev Cancer. 2012 Sep;12(9):587-98
22918414
Nature. 2009 Mar 26;458(7237):461-7
19325626
Nat Chem Biol. 2008 Nov;4(11):682-90
18936753
Nat Rev Mol Cell Biol. 2012 Jul 23;13(8):508-23
22820888
Annu Rev Cell Dev Biol. 2006;22:159-80
16753028
Science. 1998 Sep 11;281(5383):1674-7
9733514
Amino Acids. 2012 Sep;43(3):1009-24
22821267
Mol Biosyst. 2015 Jun;11(6):1487-93
25800119
Anticancer Agents Med Chem. 2008 Dec;8(8):832-6
19075565
Cell Mol Life Sci. 2012 Jan;69(2):223-45
21922196
J Proteome Res. 2014 Feb 7;13(2):915-24
24328109
Nat Rev Cancer. 2012 Dec;12(12):801-17
23175119
Science. 2015 Mar 6;347(6226):1259038
25745177
Cell Rep. 2016 May 17;15(7):1597-1610
27184836
Science. 2002 Jul 26;297(5581):547-51
12142523
Cell Cycle. 2009 Jun 1;8(11):1688-97
19448430
Proteomics. 2016 Jan;16(2):273-87
26460060
Oncotarget. 2015 Jun 30;6(18):15734-5
26119151
Mol Cell Biol. 2011 Dec;31(24):4964-77
22006019
Mol Cell. 2013 Oct 24;52(2):272-85
24055347
Cancer Res. 2010 May 15;70(10):3861-3
20406985
Sci Signal. 2013 Mar 26;6(268):rs6
23532336
Cell Rep. 2013 Jul 11;4(1):174-88
23810556
Mol Cell. 2011 Oct 21;44(2):325-40
21906983
Nature. 2009 Oct 22;461(7267):1071-8
19847258
J Proteome Res. 2013 Mar 1;12(3):1067-77
23368288
Mol Cell Proteomics. 2014 Jul;13(7):1690-704
24719451
Curr Opin Genet Dev. 2013 Apr;23(2):156-65
23312207
Mol Cell Proteomics. 2013 May;12(5):1319-34
23397111
Nat Rev Mol Cell Biol. 2013 Apr;14(4):197-210
23847781
Cell. 2012 May 11;149(4):780-94
22579283
Cell Cycle. 2013 Jun 1;12(11):1688-95
23656789
J Cancer Res Ther. 2014 Jul-Sep;10(3):469-78
25313724
Nat Rev Cancer. 2004 Mar;4(3):216-25
14993903
Sci Signal. 2010 Dec 07;3(151):rs3
21139141
N Engl J Med. 2009 Oct 8;361(15):1475-85
19812404
Nat Cell Biol. 2011 Oct 03;13(10):1161-9
21968989
Nat Rev Mol Cell Biol. 2013 Sep;14(9):563-80
23969844
Nature. 2011 Oct 30;480(7376):254-8
22037311
Nat Rev Cancer. 2008 Mar;8(3):193-204
18256616
J Cell Biol. 2010 Aug 23;190(4):491-500
20733050
Mol Cell Proteomics. 2011 Mar;10(3):M110.003590
21139048
Nat Rev Cancer. 2003 Mar;3(3):155-68
12612651
Br J Cancer. 2013 Mar 5;108(4):748-54
23361058
Front Genet. 2016 Apr 19;7:63
27148359
Nat Genet. 2012 May;44(5):598-602
22466611
Mol Cell. 2007 Dec 14;28(5):739-45
18082599
Protein Cell. 2011 Jun;2(6):456-62
21748595
J Mammary Gland Biol Neoplasia. 2012 Jun;17(2):155-64
22644111
Mol Cell. 2015 Nov 19;60(4):547-60
26590714
J Proteome Res. 2012 Oct 5;11(10):4983-91
22909323
Cell. 2006 Nov 3;127(3):635-48
17081983
Cancer Cell. 2003 May;3(5):421-9
12781359
Annu Rev Biochem. 2011;80:273-99
21548781
Nat Commun. 2015 Feb 11;6:6233
25670504
Arch Toxicol. 2013 Sep;87(9):1635-48
23943208
Proteomics Clin Appl. 2015 Apr;9(3-4):383-95
25488289
Expert Rev Proteomics. 2015 Jun;12(3):235-53
25955281
Cell Cycle. 2007 Oct 1;6(19):2344-7
17700066
Nat Rev Cancer. 2011 Jun 24;11(7):467-80
21701511
Mol Syst Biol. 2013 Dec 22;9:714
24366814
ACS Chem Biol. 2013 Jan 18;8(1):96-104
23276252
Mol Cell Proteomics. 2013 Dec;12(12):3444-52
24187339
Mol Cell. 2007 Dec 14;28(5):730-8
18082598
Biochem Soc Trans. 2009 Oct;37(Pt 5):937-53
19754430
Cell Rep. 2015 Mar 17;10(10):1778-1791
25772364
Clin Chem. 2016 Apr;62(4):551-7
26817480
FEBS Lett. 2011 Jun 6;585(11):1625-39
21570395
Cell Rep. 2012 Aug 30;2(2):419-31
22902405
Mol Cell. 2015 Oct 15;60(2):280-93
26474068
Genes Dev. 2014 Sep 15;28(18):1977-82
25189701