title: The cutting edges in DNA repair, licensing, and fidelity: DNA and RNA repair nucleases sculpt DNA to measure twice, cut once.
abstract: To avoid genome instability, DNA repair nucleases must precisely target the correct damaged substrate before they are licensed to incise. Damage identification is a challenge for all DNA damage response proteins, but especially for nucleases that cut the DNA and necessarily create a cleaved DNA repair intermediate, likely more toxic than the initial damage. How do these enzymes achieve exquisite specificity without specific sequence recognition or, in some cases, without a non-canonical DNA nucleotide? Combined structural, biochemical, and biological analyses of repair nucleases are revealing their molecular tools for damage verification and safeguarding against inadvertent incision. Surprisingly, these enzymes also often act on RNA, which deserves more attention. Here, we review protein-DNA structures for nucleases involved in replication, base excision repair, mismatch repair, double strand break repair (DSBR), and telomere maintenance: apurinic/apyrimidinic endonuclease 1 (APE1), Endonuclease IV (Nfo), tyrosyl DNA phosphodiesterase (TDP2), UV Damage endonuclease (UVDE), very short patch repair endonuclease (Vsr), Endonuclease V (Nfi), Flap endonuclease 1 (FEN1), exonuclease 1 (Exo1), RNase T and Meiotic recombination 11 (Mre11). DNA and RNA structure-sensing nucleases are essential to life with roles in DNA replication, repair, and transcription. Increasingly these enzymes are employed as advanced tools for synthetic biology and as targets for cancer prognosis and interventions. Currently their structural biology is most fully illuminated for DNA repair, which is also essential to life. How DNA repair enzymes maintain genome fidelity is one of the DNA double helix secrets missed by James Watson and Francis Crick, that is only now being illuminated though structural biology and mutational analyses. Structures reveal motifs for repair nucleases and mechanisms whereby these enzymes follow the old carpenter adage: measure twice, cut once. Furthermore, to measure twice these nucleases act as molecular level transformers that typically reshape the DNA and sometimes themselves to achieve extraordinary specificity and efficiency.
authors.affiliation: Life Science Division, 1 Cyclotron Road, Berkeley, CA 94720, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Tsutakawa
authors.affiliation: Life Science Division, 1 Cyclotron Road, Berkeley, CA 94720, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Lafrance-Vanasse
authors.affiliation: Life Science Division, 1 Cyclotron Road, Berkeley, CA 94720, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: jat@scripps.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Tainer
mesh_terms: D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D043224:Deoxyribonuclease (Pyrimidine Dimer) / Q000737:chemistry / Q000235:genetics; D043223:Deoxyribonuclease IV (Phage T4-Induced) / Q000737:chemistry / Q000235:genetics; D004706:Endodeoxyribonucleases / Q000737:chemistry / Q000235:genetics; D045585:Flap Endonucleases / Q000737:chemistry / Q000235:genetics; D006801:Humans; D009097:Multienzyme Complexes / Q000737:chemistry / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics; D009690:Nucleic Acid Conformation; D010727:Phosphoric Diester Hydrolases; D011487:Protein Conformation; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D014157:Transcription Factors; C032219:UV endonuclease; D004706:Endodeoxyribonucleases; D045585:Flap Endonucleases; C468317:FEN1 protein, human; C071421:vsr endonuclease; D043223:Deoxyribonuclease IV (Phage T4-Induced); D043224:Deoxyribonuclease (Pyrimidine Dimer); D010727:Phosphoric Diester Hydrolases; C474866:TDP2 protein, human; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: APE1; Base excision repair; Crystallography; DNA; DNA repair; DNase; Double strand break repair; EndoIV; EndoV; Endonucleases; Enzyme–DNA complex; Exo1; Exonuclease; FEN1; Genome maintenance; Magnesium; Manganese; Metals; Mismatch repair; Mre11; Nfi; Nfo; Nucleases; Nucleotide incision repair; RNA; RNase; Structure-specific nuclease; TDP2; Telomere; UVDE; Vsr; Zinc
references.citation: Science. 2006 Oct 13;314(5797):268-74
references.pmid: 16959974
references.citation: Genes Dev. 2011 May 15;25(10):1091-104
references.pmid: 21511873
references.citation: Biochemistry. 2001 Jul 31;40(30):8738-48
references.pmid: 11467933
references.citation: Curr Opin Chem Biol. 2008 Apr;12(2):250-5
references.pmid: 18261473
references.citation: Nat Struct Mol Biol. 2012 Dec;19(12):1372-7
references.pmid: 23104058
references.citation: EMBO J. 2014 Mar 3;33(5):482-500
references.pmid: 24493214
references.citation: Cold Spring Harb Symp Quant Biol. 2000;65:233-9
references.pmid: 12760037
references.citation: Anticancer Res. 2009 Jul;29(7):2453-9
references.pmid: 19596913
references.citation: Carcinogenesis. 2012 Jan;33(1):119-23
references.pmid: 22072618
references.citation: Cell Res. 2011 Jul;21(7):1052-67
references.pmid: 21383776
references.citation: Annu Rev Biochem. 1969;38:467-500
references.pmid: 4897066
references.citation: EMBO J. 2000 Jul 17;19(14):3811-21
references.pmid: 10899134
references.citation: Biol Open. 2012 Sep 15;1(9):863-73
references.pmid: 23213480
references.citation: EMBO Rep. 2002 Mar;3(3):248-54
references.pmid: 11850399
references.citation: EMBO J. 1998 Sep 1;17(17):5214-26
references.pmid: 9724657
references.citation: Mech Ageing Dev. 2012 Apr;133(4):195-202
references.pmid: 22244820
references.citation: Chem Rev. 2013 Nov 13;113(11):8620-37
references.pmid: 23972098
references.citation: Cancer Treat Rev. 2010 Aug;36(5):425-35
references.pmid: 20056333
references.citation: Mol Cell Biol. 2007 Apr;27(8):3176-86
references.pmid: 17283043
references.citation: Trends Biochem Sci. 2012 Feb;37(2):74-84
references.pmid: 22118811
references.citation: J Biol Chem. 1994 Dec 16;269(50):31390-6
references.pmid: 7989304
references.citation: DNA Repair (Amst). 2005 Dec 8;4(12):1410-20
references.pmid: 16226493
references.citation: Biochim Biophys Acta. 2000 Apr 17;1496(2-3):333-40
references.pmid: 10771101
references.citation: Nature. 2000 Jan 27;403(6768):451-6
references.pmid: 10667800
references.citation: Nature. 1974 Apr 26;248(5451):766-9
references.pmid: 4599081
references.citation: Cancer Res. 2001 Jan 1;61(1):23-6
references.pmid: 11196167
references.citation: Mol Cell. 1998 Jun;1(7):969-79
references.pmid: 9651580
references.citation: ACS Chem Biol. 2013 Jan 18;8(1):82-95
references.pmid: 23259582
references.citation: J Biol Chem. 1996 Nov 29;271(48):30672-6
references.pmid: 8940043
references.citation: Nat Commun. 2013;4:2271
references.pmid: 23912683
references.citation: Mol Cell. 1999 May;3(5):621-8
references.pmid: 10360178
references.citation: J Biol Chem. 2013 Mar 22;288(12):8445-8455
references.pmid: 23355472
references.citation: Antioxid Redox Signal. 2014 Feb 1;20(4):678-707
references.pmid: 23834463
references.citation: Nat Med. 2007 Jul;13(7):812-9
references.pmid: 17589521
references.citation: Nucleic Acids Res. 2012 Jan;40(2):914-27
references.pmid: 21937514
references.citation: Biochemistry. 1972 Sep 12;11(19):3610-8
references.pmid: 4626532
references.citation: Nat Struct Mol Biol. 2011 Apr;18(4):423-31
references.pmid: 21441914
references.citation: EMBO J. 2009 Apr 22;28(8):1111-20
references.pmid: 19279666
references.citation: J Mol Biol. 2005 Nov 11;353(5):980-9
references.pmid: 16216273
references.citation: J Biol Chem. 1998 Dec 25;273(52):35126-31
references.pmid: 9857048
references.citation: J Mol Biol. 1999 Mar 26;287(2):331-46
references.pmid: 10080896
references.citation: APMIS. 2014 Jul;122(7):663-5
references.pmid: 24164220
references.citation: J Biol Chem. 1995 Dec 1;270(48):28609-16
references.pmid: 7499377
references.citation: Nature. 2000 Oct 12;407(6805):711-7
references.pmid: 11048711
references.citation: J Biol Chem. 1987 Jul 25;262(21):9962-70
references.pmid: 3611072
references.citation: Mutat Res. 2005 Sep 4;577(1-2):55-76
references.pmid: 15941573
references.citation: Mutat Res. 2001 Jan;432(3-4):53-9
references.pmid: 11465542
references.citation: EMBO J. 2005 Feb 23;24(4):683-93
references.pmid: 15616578
references.citation: Neuroreport. 1997 Apr 14;8(6):1337-40
references.pmid: 9172131
references.citation: Cell Res. 2008 Jan;18(1):27-47
references.pmid: 18166975
references.citation: Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14634-9
references.pmid: 22908287
references.citation: J Biochem. 2009 Oct;146(4):523-6
references.pmid: 19556224
references.citation: DNA Repair (Amst). 2007 Apr 1;6(4):410-28
references.pmid: 17208522
references.citation: J Biol Chem. 1998 Apr 3;273(14):7835-42
references.pmid: 9525876
references.citation: Cell. 2011 Apr 15;145(2):198-211
references.pmid: 21496641
references.citation: Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):473-82
references.pmid: 15701830
references.citation: Cell. 1999 Dec 10;99(6):615-23
references.pmid: 10612397
references.citation: Nat Commun. 2013;4:2273
references.pmid: 23912718
references.citation: Cell. 2004 Jan 9;116(1):39-50
references.pmid: 14718165
references.citation: J Biol Chem. 1995 Mar 3;270(9):4503-8
references.pmid: 7876218
references.citation: Nucleic Acids Res. 2012 Dec;40(22):11435-49
references.pmid: 23080121
references.citation: Mol Cell Biol. 2005 Aug;25(15):6380-90
references.pmid: 16024777
references.citation: Structure. 2007 Oct;15(10):1316-24
references.pmid: 17937920
references.citation: Nat Struct Biol. 2000 Mar;7(3):176-8
references.pmid: 10700268
references.citation: Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):9924-9
references.pmid: 12119409
references.citation: Cell. 1998 Oct 2;95(1):135-46
references.pmid: 9778254
references.citation: Cell. 2008 Oct 3;135(1):97-109
references.pmid: 18854158
references.citation: Science. 1998 Feb 6;279(5352):853-6
references.pmid: 9452383
references.citation: Mol Aspects Med. 2007 Jun-Aug;28(3-4):375-95
references.pmid: 17560642
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4052-5
references.pmid: 16537483
references.citation: Nucleic Acids Res. 1997 Aug 1;25(15):2985-91
references.pmid: 9224597
references.citation: Cancer Res. 2003 Dec 15;63(24):8614-22
references.pmid: 14695172
references.citation: Proc Natl Acad Sci U S A. 1968 Apr;59(4):1300-6
references.pmid: 4870862
references.citation: Nucleic Acids Res. 2013 Jan;41(2):1363-71
references.pmid: 23221644
references.citation: Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):8919-23
references.pmid: 8799128
references.citation: Nucleic Acids Res. 2000 Oct 15;28(20):3871-9
references.pmid: 11024165
references.citation: DNA Repair (Amst). 2004 Jun 3;3(6):639-47
references.pmid: 15135731
references.citation: J Biol Chem. 2002 Aug 16;277(33):29654-61
references.pmid: 12050169
references.citation: Cell Cycle. 2010 Jul 15;9(14):2866-77
references.pmid: 20647759
references.citation: Mol Cell Biol. 2009 Apr;29(7):1834-54
references.pmid: 19188445
references.citation: J Biol Chem. 2012 Jan 20;287(4):2328-41
references.pmid: 22102415
references.citation: Curr Opin Struct Biol. 1999 Feb;9(1):37-47
references.pmid: 10047578
references.citation: J Biol Chem. 2009 Aug 14;284(33):22184-22194
references.pmid: 19525235
references.citation: Hum Mutat. 2009 Sep;30(9):1320-8
references.pmid: 19618370
references.citation: J Cell Sci. 2003 Aug 1;116(Pt 15):3051-60
references.pmid: 12829735
references.citation: J Pathol. 1998 Nov;186(3):319-24
references.pmid: 10211123
references.citation: Q Rev Biophys. 2011 Feb;44(1):1-93
references.pmid: 20854710
references.citation: Nucleic Acids Res. 1994 Aug 11;22(15):3026-32
references.pmid: 8065916
references.citation: Subcell Biochem. 2012;62:301-26
references.pmid: 22918592
references.citation: Mol Oncol. 2008 Dec;2(4):296-316
references.pmid: 19383352
references.citation: Mol Cancer Res. 2008 Nov;6(11):1710-7
references.pmid: 19010819
references.citation: Yale J Biol Med. 2013 Dec 13;86(4):517-23
references.pmid: 24348216
references.citation: Nucleic Acids Res. 2003 Nov 1;31(21):6344-53
references.pmid: 14576322
references.citation: Nature. 1995 Mar 23;374(6520):381-6
references.pmid: 7885481
references.citation: Cell. 2011 Apr 15;145(2):212-23
references.pmid: 21496642
references.citation: Genome Res. 2000 Mar;10(3):330-43
references.pmid: 10720574
references.citation: PLoS One. 2012;7(11):e47466
references.pmid: 23139746
references.citation: Proc Natl Acad Sci U S A. 1986 Oct;83(20):7731-5
references.pmid: 2429316
references.citation: Proc Natl Acad Sci U S A. 2012 May 29;109(22):8528-33
references.pmid: 22586102
references.citation: J Mol Biol. 2012 Feb 24;416(3):425-37
references.pmid: 22227386
references.citation: Nucleic Acids Res. 2004 Aug 02;32(13):4071-80
references.pmid: 15289580
references.citation: J Biol Chem. 1997 Dec 5;272(49):30774-9
references.pmid: 9388217
references.citation: Biochemistry. 2000 Aug 8;39(31):9523-32
references.pmid: 10924149
references.citation: Cell. 2011 May 13;145(4):529-42
references.pmid: 21565612
references.citation: J Biol Chem. 2001 Sep 21;276(38):35458-64
references.pmid: 11454871
references.citation: Mol Cell Biol. 2003 Sep;23(17):6063-74
references.pmid: 12917330
references.citation: Cell. 1999 Dec 10;99(6):577-87
references.pmid: 10612394
references.citation: Mutat Res. 2000 Aug 30;460(3-4):211-29
references.pmid: 10946230
references.citation: Mutat Res. 1998 Oct 21;409(1):17-29
references.pmid: 9806499
references.citation: Cell. 1999 Aug 6;98(3):397-408
references.pmid: 10458614
references.citation: Nature. 2002 Jan 10;415(6868):183-7
references.pmid: 11805838
references.citation: Nat Methods. 2013 Jun;10(6):453-4
references.pmid: 23624664
references.citation: Genes Dev. 1994 Jun 1;8(11):1344-55
references.pmid: 7926735
references.citation: J Biol Chem. 2009 Oct 9;284(41):28352-28366
references.pmid: 19674974
references.citation: Cell. 2008 May 30;133(5):789-800
references.pmid: 18510924
references.citation: Nucleic Acids Res. 1999 Jun 1;27(11):2256-64
references.pmid: 10325412
references.citation: Oncogene. 2003 Oct 16;22(46):7243-6
references.pmid: 14562054
references.citation: Nucleic Acids Res. 2013 Nov;41(21):9839-47
references.pmid: 23975198
references.citation: Cell. 1993 Sep 24;74(6):1021-31
references.pmid: 8402879
references.citation: DNA Repair (Amst). 2011 Jul 15;10(7):697-713
references.pmid: 21571596
references.citation: Trends Biochem Sci. 2003 Jul;28(7):384-90
references.pmid: 12878006
references.citation: Biochem Soc Trans. 2009 Jun;37(Pt 3):605-13
references.pmid: 19442257
references.citation: Structure. 2011 Nov 9;19(11):1591-602
references.pmid: 22078559
references.citation: Structure. 2013 Feb 5;21(2):257-65
references.pmid: 23313664
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1465-70
references.pmid: 17242363
references.citation: Mol Cell. 2014 Jan 9;53(1):7-18
references.pmid: 24316220
references.citation: Cell Mol Life Sci. 2010 Nov;67(21):3621-31
references.pmid: 20809131
references.citation: Nat Struct Mol Biol. 2008 May;15(5):515-22
references.pmid: 18408731
references.citation: Cell. 2007 May 18;129(4):665-79
references.pmid: 17512402
references.citation: Nature. 2002 Feb 7;415(6872):655-9
references.pmid: 11832948
references.citation: DNA Repair (Amst). 2007 Apr 1;6(4):470-80
references.pmid: 17116430
references.citation: Cancer Res. 2001 Jul 15;61(14):5552-7
references.pmid: 11454706
references.citation: Cell Mol Life Sci. 2010 Nov;67(21):3589-608
references.pmid: 20706766
references.citation: J Biol Chem. 2003 Jan 31;278(5):3048-54
references.pmid: 12444080
references.citation: J Mol Biol. 2008 May 23;379(1):17-27
references.pmid: 18439621
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5739-43
references.pmid: 15824325
references.citation: Nat Struct Mol Biol. 2012 Dec;19(12):1363-71
references.pmid: 23104055
references.citation: J Biol Chem. 2001 Sep 28;276(39):36295-302
references.pmid: 11477073
references.citation: Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):E3071-80
references.pmid: 23898172