Skip to content
2000
Volume 32, Issue 2
  • ISSN: 0929-8665
  • E-ISSN: 1875-5305

Abstract

Endogenous or exogenous DNA damage needs to be repaired, therefore, cells in all the three domains have repair pathways to maintain the integrity of their genetic material. Uracil DNA glycosylases (UDGs), also known as UNGs (uracil-DNA N-glycosylases), are part of the base-excision repair (BER) pathway. These enzymes specifically remove uracil from DNA molecules by cleaving the glycosidic bond between the uracil base and the deoxyribose sugar. UDGs can be broadly classified into six families, and each of them share conserved motifs that are critical for substrate recognition and catalysis. Recently, an unconventional UDG known as UDGX has been identified from the species , which is different from other UDG members in forming an irreversible and extremely stable complex with DNA that is resistant to even harsh denaturants such as SDS, NaOH, and heat. This suicide inactivation mechanism prevents uracil excision and might play a protective role in maintaining genome integrity, as bacterial survival under hypoxic conditions is reduced due to the overexpression of MsmUDGX. Additionally, due to the importance of UDGs, the number of structures has been resolved . Moreover , high-resolution 3D structures of apo MsmUDGX, as well as uracil and DNA-bound forms, are available in PDB. This review aims to provide insights into the specific structural-functional aspects of each UDG family member for theragnostic applications.

Loading

Article metrics loading...

/content/journals/ppl/10.2174/0109298665318621241128041145
2024-12-26
2025-09-04
Loading full text...

Full text loading...

References

  1. JiaQ. ZengH. TuJ. SunL. CaoW. XieW. Structural insights into an MsmUdgX mutant capable of both crosslinking and uracil excision capability.DNA Repair (Amst.)20219710300810.1016/j.dnarep.2020.10300833248387
    [Google Scholar]
  2. ParsonsJ.L. GrundyG.J. The Base Excision Repair (BER) pathway.Encyclopedia of Cell Biology.Elsevier202354155110.1016/B978‑0‑12‑821618‑7.00100‑0
    [Google Scholar]
  3. MokkapatiS.K. HenestrosaA.R. BhagwatA.S. Escherichia coli DNA glycosylase Mug: A growth-regulated enzyme required for mutation avoidance in stationary-phase cells.Mol. Microbiol.20014151101111110.1046/j.1365‑2958.2001.02559.x11555290
    [Google Scholar]
  4. MatsumotoY. ZhangQ.M. TakaoM. YasuiA. YoneiS. Escherichia coli Nth and human hNTH1 DNA glycosylases are involved in removal of 8-oxoguanine from 8-oxoguanine/guanine mispairs in DNA.Nucleic Acids Res.20012991975198110.1093/nar/29.9.197511328882
    [Google Scholar]
  5. CollinsA. Investigating oxidative DNA damage and its repair using the comet assay.Mutat. Res. Rev. Mutat. Res.20096811243210.1016/j.mrrev.2007.10.002
    [Google Scholar]
  6. HölzK. PavlicA. LietardJ. SomozaM.M. Specificity and efficiency of the uracil DNA glycosylase-mediated strand cleavage surveyed on large sequence libraries.Sci. Rep.2019911782210.1038/s41598‑019‑54044‑x31780717
    [Google Scholar]
  7. KawaiA. HiguchiS. TsunodaM. NakamuraK.T. YamagataY. MiyamotoS. Crystal structure of family 4 uracil–DNA glycosylase from Sulfolobus tokodaii and a function of tyrosine 170 in DNA binding.FEBS Lett.201558919Pt B26752682
    [Google Scholar]
  8. SchormannN. RicciardiR. ChattopadhyayD. Uracil-DNA glycosylases—Structural and functional perspectives on an essential family of DNA repair enzymes.Protein Sci.201423121667168510.1002/pro.255425252105
    [Google Scholar]
  9. DusseauC. MurrayG. KeenanR. O’KellyT. KrokanH. McLeodH. Analysis of uracil DNA glycosylase in human colorectal cancer.Int. J. Oncol.200118239339910.3892/ijo.18.2.39311172609
    [Google Scholar]
  10. KimY.J. WilsonD.M., III. Overview of base excision repair biochemistry.Curr. Mol. Pharmacol.20125131310.2174/187446721120501000322122461
    [Google Scholar]
  11. SavvaR. The essential co-option of uracil-DNA glycosylases by herpesviruses invites novel antiviral design.Microorganisms20208346110.3390/microorganisms803046132214054
    [Google Scholar]
  12. Mendes-PereiraA.M. MartinS.A. BroughR. McCarthyA. TaylorJ.R. KimJ.S. WaldmanT. LordC.J. AshworthA. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors.EMBO Mol. Med.200916-731532210.1002/emmm.20090004120049735
    [Google Scholar]
  13. ParikhS.S. MolC.D. SlupphaugG. BharatiS. KrokanH.E. TainerJ.A. Base excision repair initiation revealed by crystal structures and binding kinetics of human uracil-DNA glycosylase with DNA.EMBO J.199817175214522610.1093/emboj/17.17.52149724657
    [Google Scholar]
  14. HandaP. AcharyaN. VarshneyU. Effects of mutations at tyrosine 66 and asparagine 123 in the active site pocket of Escherichia coli uracil DNA glycosylase on uracil excision from synthetic DNA oligomers: Evidence for the occurrence of long-range interactions between the enzyme and substrate.Nucleic Acids Res.200230143086309510.1093/nar/gkf42512136091
    [Google Scholar]
  15. GallinariP. JiricnyJ. A new class of uracil-DNA glycosylases related to human thymine-DNA glycosylase.Nature1996383660273573810.1038/383735a08878487
    [Google Scholar]
  16. NeddermannP. JiricnyJ. Efficient removal of uracil from G.U mispairs by themismatch-specific thymine DNA glycosylase from HeLa cells.Proc. Natl. Acad. Sci.19949151642164610.1073/pnas.91.5.16428127859
    [Google Scholar]
  17. MoeE. LeirosI. SmalåsA.O. McSweeneyS. The crystal structure of mismatch-specific uracil-DNA glycosylase (MUG) from Deinococcus radiodurans reveals a novel catalytic residue and broad substrate specificity.J. Biol. Chem.2006281156957710.1074/jbc.M50803220016223719
    [Google Scholar]
  18. WibleyJ.E.A. WatersT.R. HaushalterK. VerdineG.L. PearlL.H. Structure and specificity of the vertebrate anti-mutator uracil-DNA glycosylase SMUG1.Mol. Cell20031161647165910.1016/S1097‑2765(03)00235‑112820976
    [Google Scholar]
  19. PettersenH.S. SundheimO. GilljamK.M. SlupphaugG. KrokanH.E. KavliB. Uracil–DNA glycosylases SMUG1 and UNG2 coordinate the initial steps of base excision repair by distinct mechanisms.Nucleic Acids Res.200735123879389210.1093/nar/gkm37217537817
    [Google Scholar]
  20. HosekiJ. OkamotoA. MasuiR. ShibataT. InoueY. YokoyamaS. KuramitsuS. Crystal structure of a family 4 uracil-DNA glycosylase from Thermus thermophilus HB8.J. Mol. Biol.2003333351552610.1016/j.jmb.2003.08.03014556741
    [Google Scholar]
  21. KosakaH. HosekiJ. NakagawaN. KuramitsuS. MasuiR. Crystal structure of family 5 uracil-DNA glycosylase bound to DNA.J. Mol. Biol.2007373483985010.1016/j.jmb.2007.08.02217870091
    [Google Scholar]
  22. ChungJ.H. ImE.K. ParkH.Y. KwonJ.H. LeeS. OhJ. HwangK.C. LeeJ.H. JangY. A novel uracil-DNA glycosylase family related to the helix-hairpin-helix DNA glycosylase superfamily.Nucleic Acids Res.20033182045205510.1093/nar/gkg31912682355
    [Google Scholar]
  23. LeeH.W. DominyB.N. CaoW. New family of deamination repair enzymes in uracil-DNA glycosylase superfamily.J. Biol. Chem.201128636312823128710.1074/jbc.M111.24952421642431
    [Google Scholar]
  24. BarrettT.E. SavvaR. PanayotouG. BarlowT. BrownT. JiricnyJ. PearlL.H. Crystal structure of a G:T/U mismatch-specific DNA glycosylase: Mismatch recognition by complementary-strand interactions.Cell199892111712910.1016/S0092‑8674(00)80904‑69489705
    [Google Scholar]
  25. YangH. Fitz-GibbonS. MarcotteE.M. TaiJ.H. HymanE.C. MillerJ.H. Characterization of a thermostable DNA glycosylase specific for U/G and T/G mismatches from the hyperthermophilic archaeon Pyrobaculum aerophilum. J. Bacteriol.200018251272127910.1128/JB.182.5.1272‑1279.200010671447
    [Google Scholar]
  26. AhnW.C. AroliS. KimJ.H. MoonJ.H. LeeG.S. LeeM.H. SangP.B. OhB.H. VarshneyU. WooE.J. Covalent binding of uracil DNA glycosylase UdgX to abasic DNA upon uracil excision.Nat. Chem. Biol.201915660761410.1038/s41589‑019‑0289‑331101917
    [Google Scholar]
  27. KrokanH.E. StandalR. SlupphaugG. DNA glycosylases in the base excision repair of DNA.Biochem. J.1997325111610.1042/bj32500019224623
    [Google Scholar]
  28. DalhusB. ArvaiA.S. RosnesI. OlsenØ.E. BackeP.H. AlsethI. GaoH. CaoW. TainerJ.A. BjøråsM. Structures of endonuclease V with DNA reveal initiation of deaminated adenine repair.Nat. Struct. Mol. Biol.200916213814310.1038/nsmb.153819136958
    [Google Scholar]
  29. SvilarD. GoellnerE.M. AlmeidaK.H. SobolR.W. Base excision repair and lesion-dependent subpathways for repair of oxidative DNA damage.Antioxid. Redox Signal.201114122491250710.1089/ars.2010.346620649466
    [Google Scholar]
  30. MuselmaniW. Kashif-KhanN. BagnérisC. SantangeloR. WilliamsM.A. SavvaR. A multimodal approach towards genomic identification of protein inhibitors of uracil-DNA glycosylase.Viruses2023156134810.3390/v1506134837376646
    [Google Scholar]
  31. ParikhS.S. PutnamC.D. TainerJ.A. Lessons learned from structural results on uracil-DNA glycosylase.Mutat. Res. DNA Repair20004603-418319910.1016/S0921‑8777(00)00026‑410946228
    [Google Scholar]
  32. LeeD.H. LiuY. LeeH.W. XiaB. BriceA.R. ParkS.H. BaldufH. DominyB.N. CaoW. A structural determinant in the uracil DNA glycosylase superfamily for the removal of uracil from adenine/uracil base pairs.Nucleic Acids Res.20154321081108910.1093/nar/gku133225550433
    [Google Scholar]
  33. VallièresC. BenoitO. GuittetO. HuangM.E. LepoivreM. Golinelli-CohenM.P. VernisL. Iron-sulfur protein odyssey: exploring their cluster functional versatility and challenging identification.Metallomics2024165mfae02510.1093/mtomcs/mfae02538744662
    [Google Scholar]
  34. SangP.B. SrinathT. PatilA.G. WooE.J. VarshneyU. A unique uracil-DNA binding protein of the uracil DNA glycosylase superfamily.Nucleic Acids Res.201543178452846310.1093/nar/gkv85426304551
    [Google Scholar]
  35. SavvaR. Targeting uracil-DNA glycosylases for therapeutic outcomes using insights from virus evolution.Future Med. Chem.201911111323134410.4155/fmc‑2018‑031931161802
    [Google Scholar]
  36. BerraC.M. TorrezanG.T. de PaulaC.A. HsiehR. LourençoS.V. CarraroD.M. Use of uracil-DNA glycosylase enzyme to reduce DNA-related artifacts from formalin-fixed and paraffin-embedded tissues in diagnostic routine.Applied Cancer Research2019391710.1186/s41241‑019‑0075‑2
    [Google Scholar]
  37. LadnerR. The role of dUTPase and uracil-DNA repair in cancer chemotherapy.Curr. Protein Pept. Sci.20012436137010.2174/138920301338099112374095
    [Google Scholar]
  38. TingH. KouzminovaE.A. KuzminovA. Synthetic lethality with the dut defect in Escherichia coli reveals layers of DNA damage of increasing complexity due to uracil incorporation.J. Bacteriol.2008190175841585410.1128/JB.00711‑0818586941
    [Google Scholar]
  39. HuehlsA.M. HuntoonC.J. JoshiP.M. BaehrC.A. WagnerJ.M. WangX. LeeM.Y. KarnitzL.M. Genomically incorporated 5-fluorouracil that escapes UNG-initiated base excision repair blocks DNA replication and activates homologous recombination.Mol. Pharmacol.2016891536210.1124/mol.115.10016426494862
    [Google Scholar]
  40. ConteducaV. MoscaA. BrighiN. de GiorgiU. RescignoP. New prognostic biomarkers in metastatic castration-resistant prostate cancer.Cells202110119310.3390/cells1001019333478015
    [Google Scholar]
  41. StewartJ. WeiS. DattaM. VarshneyU. BhagwatA. Abstract 3802: A novel uracil-DNA glycosylase, UdgX, as a new biochemical tool to directly detect uracils in DNA.Cancer Res.20177713 Suppl3802380210.1158/1538‑7445.AM2017‑3802
    [Google Scholar]
  42. ChenR. WangH. ManskyL.M. Roles of uracil-DNA glycosylase and dUTPase in virus replication.J. Gen. Virol.200283102339234510.1099/0022‑1317‑83‑10‑233912237414
    [Google Scholar]
  43. MinkahN. MacalusoM. OldenburgD.G. PadenC.R. WhiteD.W. McBrideK.M. KrugL.T. Absence of the uracil DNA glycosylase of murine gammaherpesvirus 68 impairs replication and delays the establishment of latency in vivo. J. Virol.20158963366337910.1128/JVI.03111‑1425589640
    [Google Scholar]
  44. BoganiF. BoehmerP.E. The replicative DNA polymerase of herpes simplex virus 1 exhibits apurinic/apyrimidinic and 5′-deoxyribose phosphate lyase activities.Proc. Natl. Acad. Sci. USA200810533117091171410.1073/pnas.080637510518695225
    [Google Scholar]
  45. KingJ.J. BorzooeeF. ImJ. AsgharpourM. GhorbaniA. DiamondC.P. FifieldH. BerghuisL. LarijaniM. Structure-based design of first-generation small molecule inhibitors targeting the catalytic pockets of AID, APOBEC3A, and APOBEC3B.ACS Pharmacol. Transl. Sci.2021441390140710.1021/acsptsci.1c0009134423273
    [Google Scholar]
  46. StewartJ.A. DamaniaB. Human DNA tumor viruses evade uracil-mediated antiviral immunity.PLoS Pathog.2023193e101125210.1371/journal.ppat.101125236996040
    [Google Scholar]
  47. KavliB. AndersenS. OtterleiM. LiabakkN.B. ImaiK. FischerA. DurandyA. KrokanH.E. SlupphaugG. B cells from hyper-IgM patients carrying UNG mutations lack ability to remove uracil from ssDNA and have elevated genomic uracil.J. Exp. Med.2005201122011202110.1084/jem.2005004215967827
    [Google Scholar]
  48. VisnesT. DosethB. PettersenH.S. HagenL. SousaM.M.L. AkbariM. OtterleiM. KavliB. SlupphaugG. KrokanH.E. Uracil in DNA and its processing by different DNA glycosylases.Philos. Trans. R. Soc. Lond. B Biol. Sci.2009364151756356810.1098/rstb.2008.018619008197
    [Google Scholar]
  49. MechetinG.V. EndutkinA.V. DiatlovaE.A. ZharkovD.O. Inhibitors of DNA glycosylases as prospective drugs.Int. J. Mol. Sci.2020219311810.3390/ijms2109311832354123
    [Google Scholar]
  50. JiangY.L. KroskyD.J. SeipleL. StiversJ.T. Uracil-directed ligand tethering: An efficient strategy for uracil DNA glycosylase (UNG) inhibitor development.J. Am. Chem. Soc.200512749174121742010.1021/ja055846n16332091
    [Google Scholar]
  51. JiangY.L. ChungS. KroskyD.J. StiversJ.T. Synthesis and high-throughput evaluation of triskelion uracil libraries for inhibition of human dUTPase and UNG2.Bioorg. Med. Chem.200614165666567210.1016/j.bmc.2006.04.02216678429
    [Google Scholar]
  52. ZhangH. ZhangL. JiangJ. YuR. A highly sensitive electrochemical platform for the assay of uracil-DNA glycosylase activity combined with enzymatic amplification.Anal. Sci.201329219319810.2116/analsci.29.19323400284
    [Google Scholar]
  53. SpeinaE. CieślaJ.M. GraziewiczM.A. LavalJ. KazimierczukZ. TudekB. Inhibition of DNA repair glycosylases by base analogs and tryptophan pyrolysate, Trp-P-1.Acta Biochim. Pol.200552116717810.18388/abp.2005_350315827615
    [Google Scholar]
  54. EberleR.J. CoronadoM.A. PeinadoR.S. de MoraesF.R. OlivierD. DreyerT. de Oliveira LopesD. da LuzB.S.R. AzevedoV. ArniR.K. The polyanions heparin and suramin impede binding of free adenine to a DNA glycosylase from C. pseudotuberculosis.Int. J. Biol. Macromol.201912545946810.1016/j.ijbiomac.2018.12.06730529553
    [Google Scholar]
  55. ChetsangaC.J. Excision of aflatoxin B 1 -imidazole ring opened guanine adducts from DNA by formamidopyrimidine-DNA glycosylase.Carcinogenesis198348997100010.1016/j.ijbiomac.2018.12.06730529553
    [Google Scholar]
  56. LataK. AfsarM. RamachandranR. Biochemical characterization and novel inhibitor identification of Mycobacterium tuberculosis Endonuclease VIII 2 (Rv3297).Biochem. Biophys. Rep.201712202810.1016/j.bbrep.2017.07.01028955788
    [Google Scholar]
  57. HuberK.V.M. SalahE. RadicB. GridlingM. ElkinsJ.M. StukalovA. JemthA.S. GöktürkC. SanjivK. StrömbergK. PhamT. BerglundU.W. ColingeJ. BennettK.L. LoizouJ.I. HelledayT. KnappS. Superti-FurgaG. Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy.Nature2014508749522222710.1038/nature1319424695225
    [Google Scholar]
  58. VisnesT. Cázares-KörnerA. HaoW. WallnerO. MasuyerG. LosevaO. MortusewiczO. WiitaE. SarnoA. ManoilovA. Astorga-WellsJ. JemthA.S. PanL. SanjivK. KarstenS. GokturkC. GrubeM. HomanE.J. HannaB.M.F. PaulinC.B.J. PhamT. RastiA. BerglundU.W. von NicolaiC. Benitez-BuelgaC. KoolmeisterT. IvanicD. IlievP. ScobieM. KrokanH.E. BaranczewskiP. ArturssonP. AltunM. JensenA.J. KalderénC. BaX. ZubarevR.A. StenmarkP. BoldoghI. HelledayT. Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation.Science2018362641683483910.1126/science.aar804830442810
    [Google Scholar]
  59. BliksrudY.T. EllingsenA. BjøråsM. Fumarylacetoacetate inhibits the initial step of the base excision repair pathway: Implication for the pathogenesis of tyrosinemia type I.J. Inherit. Metab. Dis.201336577377810.1007/s10545‑012‑9556‑023138988
    [Google Scholar]
  60. DixonM. WoodrickJ. GuptaS. KarmahapatraS.K. DevitoS. VasudevanS. DakshanamurthyS. AdhikariS. YenugondaV.M. RoyR. Naturally occurring polyphenol, morin hydrate, inhibits enzymatic activity of N-methylpurine DNA glycosylase, a DNA repair enzyme with various roles in human disease.Bioorg. Med. Chem.20152351102111110.1016/j.bmc.2014.12.06725650313
    [Google Scholar]
  61. AroliS. WooE.J. GopalB. VarshneyU. Mutational and structural analyses of UdgX: insights into the active site pocket architecture and its evolution.Nucleic Acids Res.202351136554656510.1093/nar/gkad48637283083
    [Google Scholar]
  62. DattaM. AroliS. KarmakarK. DuttaS. ChakravorttyD. VarshneyU. Development of mCherry tagged UdgX as a highly sensitive molecular probe for specific detection of uracils in DNA.Biochem. Biophys. Res. Commun.20195181384310.1016/j.bbrc.2019.08.00531402116
    [Google Scholar]
  63. TaharaY. KietrysA.M. HebenbrockM. LeeY. WilsonD.L. KoolE.T. Dual inhibitors of 8-oxoguanine surveillance by OGG1 and NUDT1.ACS Chem. Biol.201914122606261510.1021/acschembio.9b0049031622553
    [Google Scholar]
  64. KomiyaE. TakamatsuS. MiuraD. TsukakoshiK. TsugawaW. SodeK. IkebukuroK. AsanoR. Exploration and application of DNA-binding proteins to make a versatile DNA–protein covalent-linking patch (D-Pclip): The case of a biosensing element.J. Am. Chem. Soc.202414664087409710.1021/jacs.3c1266838295327
    [Google Scholar]
/content/journals/ppl/10.2174/0109298665318621241128041145
Loading
/content/journals/ppl/10.2174/0109298665318621241128041145
Loading

Data & Media loading...


  • Article Type:
    Review Article
Keyword(s): Base-excision repair; diagnostics; R-loop; structure; UDGX; uracil DNA glycosylases
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test