Skip to main content

Advertisement

SpringerLink
Log in

The base excision repair process: comparison between higher and lower eukaryotes

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The base excision repair (BER) pathway is essential for maintaining the stability of DNA in all organisms and defects in this process are associated with life-threatening diseases. It is involved in removing specific types of DNA lesions that are induced by both exogenous and endogenous genotoxic substances. BER is a multi-step mechanism that is often initiated by the removal of a damaged base leading to a genotoxic intermediate that is further processed before the reinsertion of the correct nucleotide and the restoration of the genome to a stable structure. Studies in human and yeast cells, as well as fruit fly and nematode worms, have played important roles in identifying the components of this conserved DNA repair pathway that maintains the integrity of the eukaryotic genome. This review will focus on the components of base excision repair, namely, the DNA glycosylases, the apurinic/apyrimidinic endonucleases, the DNA polymerase, and the ligases, as well as other protein cofactors. Functional insights into these conserved proteins will be provided from humans, Saccharomyces cerevisiae, Drosophila melanogaster, and Caenorhabditis elegans, and the implications of genetic polymorphisms and knockouts of the corresponding genes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Tubbs A, Nussenzweig A (2017) Endogenous DNA damage as a source of genomic instability in cancer. Cell 168(4):644–656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Matkarimov BT, Saparbaev MK (2020) DNA repair and mutagenesis in vertebrate mitochondria: evidence for asymmetric DNA strand inheritance. Adv Exp Med Biol 1241:77–100

    Article  CAS  PubMed  Google Scholar 

  3. Tremblay S, Wagner JR (2008) Dehydration, deamination and enzymatic repair of cytosine glycols from oxidized poly(dG-dC) and poly(dI-dC). Nucleic Acids Res 36(1):284–293

    Article  CAS  PubMed  Google Scholar 

  4. Boiteux S, Coste F, Castaing B (2017) Repair of 8-oxo-7,8-dihydroguanine in prokaryotic and eukaryotic cells: Properties and biological roles of the Fpg and OGG1 DNA N-glycosylases. Free Radic Biol Med 107:179–201

    Article  CAS  PubMed  Google Scholar 

  5. Slyskova J et al (2018) Base and nucleotide excision repair facilitate resolution of platinum drugs-induced transcription blockage. Nucleic Acids Res 46(18):9537–9549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bauer NC, Corbett AH, Doetsch PW (2015) The current state of eukaryotic DNA base damage and repair. Nucleic Acids Res 43(21):10083–10101

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Chatterjee N, Walker GC (2017) Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen 58(5):235–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Moor NA, Lavrik OI (2018) Protein–protein interactions in DNA base excision repair. Biochemistry (Mosc) 83(4):411–422

    Article  CAS  Google Scholar 

  9. Beard WA et al (2019) Eukaryotic base excision repair: new approaches shine light on mechanism. Annu Rev Biochem 88:137–162

    Article  CAS  PubMed  Google Scholar 

  10. Ayyildiz D et al (2020) Architecture of the human ape1 interactome defines novel cancers signatures. Sci Rep 10(1):28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Boiteux S, Jinks-Robertson S (2013) DNA repair mechanisms and the bypass of DNA damage in Saccharomyces cerevisiae. Genetics 193(4):1025–1064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ljungquist S, Andersson A, Lindahl T (1974) A mammalian endonuclease specific for apurinic sites in double-stranded deoxyribonucleic acid. II. Further studies on the substrate specificity. J Biol Chem 249(5):1536–1540

    Article  CAS  PubMed  Google Scholar 

  13. Muench KF, Misra RP, Humayun MZ (1983) Sequence specificity in aflatoxin B1–DNA interactions. Proc Natl Acad Sci USA 80(1):6–10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 362(6422):709–715

    Article  CAS  PubMed  Google Scholar 

  15. Ruf A, de Murcia G, Schulz GE (1998) Inhibitor and NAD+ binding to poly(ADP-ribose) polymerase as derived from crystal structures and homology modeling. Biochemistry 37(11):3893–3900

    Article  CAS  PubMed  Google Scholar 

  16. Sobol RW et al (2000) The lyase activity of the DNA repair protein beta-polymerase protects from DNA-damage-induced cytotoxicity. Nature 405(6788):807–810

    Article  CAS  PubMed  Google Scholar 

  17. Mitra S et al (2002) Choreography of oxidative damage repair in mammalian genomes. Free Radic Biol Med 33(1):15–28

    Article  CAS  PubMed  Google Scholar 

  18. Caldecott KW (2020) Mammalian DNA base excision repair: Dancing in the moonlight. DNA Repair (Amst) 93:102921

    Article  CAS  Google Scholar 

  19. Drohat AC, Coey CT (2016) Role of base excision “Repair” enzymes in erasing epigenetic marks from DNA. Chem Rev 116(20):12711–12729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Boldinova EO et al (2019) Isoforms of base excision repair enzymes produced by alternative splicing. Int J Mol Sci 20(13):3279

    Article  CAS  PubMed Central  Google Scholar 

  21. Demple B, Harrison L (1994) Repair of oxidative damage to DNA: enzymology and biology. Annu Rev Biochem 63:915–948

    Article  CAS  PubMed  Google Scholar 

  22. Muha V et al (2012) Uracil-containing DNA in Drosophila: stability, stage-specific accumulation, and developmental involvement. PLoS Genet 8(6):e1002738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Elsakrmy N, Zhang-Akiyama Q-M, Ramotar D (2020) The base excision repair pathway in the nematode caenorhabditis elegans. Front Cell Dev Biol 8(1447)

  24. Lucas-Lledo JI, Maddamsetti R, Lynch M (2011) Phylogenomic analysis of the uracil-DNA glycosylase superfamily. Mol Biol Evol 28(3):1307–1317

    Article  CAS  PubMed  Google Scholar 

  25. Jacobs AL, Schar P (2012) DNA glycosylases: in DNA repair and beyond. Chromosoma 121(1):1–20

    Article  CAS  PubMed  Google Scholar 

  26. Sarno A et al (2019) Uracil-DNA glycosylase UNG1 isoform variant supports class switch recombination and repairs nuclear genomic uracil. Nucleic Acids Res 47(9):4569–4585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pettersen HS et al (2007) Uracil-DNA glycosylases SMUG1 and UNG2 coordinate the initial steps of base excision repair by distinct mechanisms. Nucleic Acids Res 35(12):3879–3892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Elateri I et al (2003) hSMUG1 can functionally compensate for Ung1 in the yeast Saccharomyces cerevisiae. DNA Repair (Amst) 2(3):315–323

    Article  CAS  Google Scholar 

  29. Schormann N, Ricciardi R, Chattopadhyay D (2014) Uracil-DNA glycosylases-structural and functional perspectives on an essential family of DNA repair enzymes. Protein Sci 23(12):1667–1685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Weiser BP et al (2018) N-terminal domain of human uracil DNA glycosylase (hUNG2) promotes targeting to uracil sites adjacent to ssDNA-dsDNA junctions. Nucleic Acids Res 46(14):7169–7178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu Z et al (2016) Hydrogen peroxide mediated mitochondrial UNG1-PRDX3 interaction and UNG1 degradation. Free Radic Biol Med 99:54–62

    Article  CAS  PubMed  Google Scholar 

  32. Papaluca A et al (2018) UNG-1 and APN-1 are the major enzymes to efficiently repair 5-hydroxymethyluracil DNA lesions in C elegans. Sci Rep 8(1):6860

    Article  PubMed  PubMed Central  Google Scholar 

  33. Bekesi A et al (2007) A novel fruitfly protein under developmental control degrades uracil-DNA. Biochem Biophys Res Commun 355(3):643–648

    Article  CAS  PubMed  Google Scholar 

  34. Kuznetsova AA et al (2017) Pre-steady-state kinetic analysis of damage recognition by human single-strand selective monofunctional uracil-DNA glycosylase SMUG1. Mol Biosyst 13(12):2638–2649

    Article  CAS  PubMed  Google Scholar 

  35. An MJ et al (2021) Ablation of SMUG1 Reduces Cell Viability and Increases UVC-Mediated Apoptosis in Hepatocarcinoma HepG2 Cells. Genes (Basel) 12(2)

  36. Kroustallaki P et al (2019) (2019) SMUG1 promotes telomere maintenance through telomerase RNA Processing. Cell Rep 28(7):1690–1702

    Article  CAS  PubMed  Google Scholar 

  37. Zhang Z et al (2016) Structural basis of substrate specificity in geobacter metallireducens SMUG1. ACS Chem Biol 11(6):1729–1736

    Article  CAS  PubMed  Google Scholar 

  38. Alsoe L et al (2017) Uracil accumulation and mutagenesis dominated by cytosine deamination in CpG dinucleotides in mice lacking UNG and SMUG1. Sci Rep 7(1):7199

    Article  PubMed  PubMed Central  Google Scholar 

  39. Dingler FA et al (2014) Uracil excision by endogenous SMUG1 glycosylase promotes efficient Ig class switching and impacts on A: T substitutions during somatic mutation. Eur J Immunol 44(7):1925–1935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kemmerich K et al (2012) Germline ablation of SMUG1 DNA glycosylase causes loss of 5-hydroxymethyluracil- and UNG-backup uracil-excision activities and increases cancer predisposition of Ung-/-Msh2-/- mice. Nucleic Acids Res 40(13):6016–6025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Abdel-Fatah TM et al (2013) Single-strand selective monofunctional uracil-DNA glycosylase (SMUG1) deficiency is linked to aggressive breast cancer and predicts response to adjuvant therapy. Breast Cancer Res Treat 142(3):515–527

    Article  CAS  PubMed  Google Scholar 

  42. Zhong J et al (2020) A Transcriptome-wide association study identifies novel candidate susceptibility genes for pancreatic cancer. J Natl Cancer Inst 112(10):1003–1012

    Article  PubMed  PubMed Central  Google Scholar 

  43. Dodd T et al (2018) Uncovering universal rules governing the selectivity of the archetypal DNA glycosylase TDG. Proc Natl Acad Sci USA 115(23):5974–5979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Popov AV et al (2019) Reading targeted DNA damage in the active demethylation pathway: role of accessory domains of eukaryotic AP endonucleases and thymine-DNA glycosylases. J Mol Biol

  45. Pidugu LS et al (2019) Excision of 5-carboxylcytosine by thymine DNA glycosylase. J Am Chem Soc 141(47):18851–18861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bellacosa A, Drohat AC (2015) Role of base excision repair in maintaining the genetic and epigenetic integrity of CpG sites. DNA Repair (Amst) 32:33–42

    Article  CAS  Google Scholar 

  47. DeNizio JE et al (2021) TET-TDG active DNA demethylation at CpG and non-CpG sites. J Mol Biol 433(8):166877

    Article  CAS  PubMed  Google Scholar 

  48. Deckard CE, Banerjee DR, Sczepanski JT (2019) Chromatin structure and the pioneering transcription factor FOXA1 regulate TDG-mediated removal of 5-formylcytosine from DNA. J Am Chem Soc 141(36):14110–14114

    Article  CAS  PubMed  Google Scholar 

  49. Cortazar D et al (2011) Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature 470(7334):419–423

    Article  CAS  PubMed  Google Scholar 

  50. Hardeland U et al (2003) The versatile thymine DNA-glycosylase: a comparative characterization of the human, Drosophila and fission yeast orthologs. Nucleic Acids Res 31(9):2261–2271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Porat N et al (2011) Direct detection of chicken genomic DNA for gender determination by thymine-DNA glycosylase. Br Poult Sci 52(1):58–65

    Article  CAS  PubMed  Google Scholar 

  52. Williams, S.C. and J.L. Parsons, NTH1 Is a New Target for Ubiquitylation-Dependent Regulation by TRIM26 Required for the Cellular Response to Oxidative Stress. Mol Cell Biol, 2018. 38(12).

  53. Denver DR, Swenson SL, Lynch M (2003) An evolutionary analysis of the helix-hairpin-helix superfamily of DNA repair glycosylases. Mol Biol Evol 20(10):1603–1611

    Article  CAS  PubMed  Google Scholar 

  54. Morinaga H et al (2009) Purification and characterization of Caenorhabditis elegans NTH, a homolog of human endonuclease III: essential role of N-terminal region. DNA Repair (Amst) 8(7):844–851

    Article  CAS  Google Scholar 

  55. Stehling O et al (2012) MMS19 assembles iron-sulfur proteins required for DNA metabolism and genomic integrity. Science 337(6091):195–199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Shinmura K et al (2019) Defective repair capacity of variant proteins of the DNA glycosylase NTHL1 for 5-hydroxyuracil, an oxidation product of cytosine. Free Radic Biol Med 131:264–273

    Article  CAS  PubMed  Google Scholar 

  57. Swartzlander DB et al (2016) Identification of SUMO modification sites in the base excision repair protein, Ntg1. DNA Repair (Amst) 48:51–62

    Article  CAS  Google Scholar 

  58. Gellon L et al (2001) Synergism between base excision repair, mediated by the DNA glycosylases Ntg1 and Ntg2, and nucleotide excision repair in the removal of oxidatively damaged DNA bases in Saccharomyces cerevisiae. Mol Genet Genomics 265(6):1087–1096

    Article  CAS  PubMed  Google Scholar 

  59. Das, L., V.G. Quintana, and J.B. Sweasy, NTHL1 in genomic integrity, aging and cancer. DNA Repair (Amst), 2020. 93: p. 102920.

  60. Lu J, Liu Y (2010) Deletion of Ogg1 DNA glycosylase results in telomere base damage and length alteration in yeast. EMBO J 29(2):398–409

    Article  CAS  PubMed  Google Scholar 

  61. Yasukawa T et al (2015) Drosophila Ogg1 is required to suppress 8-oxo-guanine accumulation following oxidative stress. Genes Genet Syst 90(1):11–20

    Article  CAS  PubMed  Google Scholar 

  62. Zhou X et al (2016) OGG1 is essential in oxidative stress induced DNA demethylation. Cell Signal 28(9):1163–1171

    Article  CAS  PubMed  Google Scholar 

  63. Ferino, A. and L.E. Xodo, Effect of DNA Glycosylases OGG1 and Neil1 on Oxidized G-Rich Motif in the KRAS Promoter. Int J Mol Sci, 2021. 22(3).

  64. Ogawa A et al (2015) Enzyme kinetics of an alternative splicing isoform of mitochondrial 8-oxoguanine DNA glycosylase, ogg1-1b, and compared with the nuclear ogg1-1a. J Biochem Mol Toxicol 29(2):49–56

    Article  CAS  PubMed  Google Scholar 

  65. Ramdzan, Z.M., et al., CUT Domains Stimulate Pol beta Enzymatic Activities to Accelerate Completion of Base Excision Repair. J Mol Biol, 2021. 433(4): p. 166806.

  66. Kaur S et al (2018) CUX1 stimulates APE1 enzymatic activity and increases the resistance of glioblastoma cells to the mono-alkylating agent temozolomide. Neuro Oncol 20(4):484–493

    Article  CAS  PubMed  Google Scholar 

  67. Pao PC et al (2020) HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease. Nat Commun 11(1):2484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Koger N et al (2019) Analysis of MUTYH alternative transcript expression, promoter function, and the effect of human genetic variants. Hum Mutat 40(4):472–482

    Article  PubMed  Google Scholar 

  69. Tan J et al (2020) An ordered assembly of MYH glycosylase, SIRT6 protein deacetylase, and Rad9-Rad1-Hus1 checkpoint clamp at oxidatively damaged telomeres. Aging (Albany NY) 12(18):17761–17785

    Article  CAS  Google Scholar 

  70. Thibodeau, M.L., et al., Base excision repair deficiency signatures implicate germline and somatic MUTYH aberrations in pancreatic ductal adenocarcinoma and breast cancer oncogenesis. Cold Spring Harb Mol Case Stud, 2019. 5(2).

  71. Isoda T et al (2014) Abnormality in Wnt signaling is causatively associated with oxidative stress-induced intestinal tumorigenesis in MUTYH-null mice. Int J Biol Sci 10(8):940–947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Felicio PS et al (2021) Whole-exome sequencing of non-BRCA1/BRCA2 mutation carrier cases at high-risk for hereditary breast/ovarian cancer. Hum Mutat 42(3):290–299

    Article  CAS  PubMed  Google Scholar 

  73. Sekelsky J (2017) DNA Repair in Drosophila: Mutagens, Models, and Missing Genes. Genetics 205(2):471–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ishchenko AA et al (2005) The 3’->5’ exonuclease of Apn1 provides an alternative pathway to repair 7,8-dihydro-8-oxodeoxyguanosine in Saccharomyces cerevisiae. Mol Cell Biol 25(15):6380–6390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yakovlev DA et al (2017) Search for Modified DNA Sites with the Human Methyl-CpG-Binding Enzyme MBD4. Acta Naturae 9(1):88–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yu AM et al (2016) The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury. Oncotarget 7(19):28624–28636

    Article  PubMed  PubMed Central  Google Scholar 

  77. Zhang Y et al (2018) Epigenetic silencing of RNF144A expression in breast cancer cells through promoter hypermethylation and MBD4. Cancer Med 7(4):1317–1325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Repo P et al (2020) Germline loss-of-function variants in MBD4 are rare in Finnish patients with uveal melanoma. Pigment Cell Melanoma Res 33(5):756–762

    Article  CAS  PubMed  Google Scholar 

  79. Sanders MA et al (2018) MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML. Blood 132(14):1526–1534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Fleming AM, Burrows CJ (2017) Formation and processing of DNA damage substrates for the hNEIL enzymes. Free Radic Biol Med 107:35–52

    Article  CAS  PubMed  Google Scholar 

  81. Albelazi, M.S., et al., The Biochemical Role of the Human NEIL1 and NEIL3 DNA Glycosylases on Model DNA Replication Forks. Genes (Basel), 2019. 10(4).

  82. Eckenroth, B.E., et al., Unique Structural Features of Mammalian NEIL2 DNA Glycosylase Prime Its Activity for Diverse DNA Substrates and Environments. Structure, 2021. 29(1): p. 29–42 e4.

  83. Li N et al (2020) Cooperation of the NEIL3 and Fanconi anemia/BRCA pathways in interstrand crosslink repair. Nucleic Acids Res 48(6):3014–3028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Rodriguez AA et al (2020) An autoinhibitory role for the GRF zinc finger domain of DNA glycosylase NEIL3. J Biol Chem 295(46):15566–15575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Fu D, Samson LD (2012) Direct repair of 3, N(4)-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase. DNA Repair (Amst) 11(1):46–52

    Article  CAS  Google Scholar 

  86. Troll, C.J., et al., Interplay between base excision repair activity and toxicity of 3-methyladenine DNA glycosylases in an E coli complementation system. Mutat Res, 2014. 763: p. 64–73.

  87. Fosmark S et al (2017) APNG as a prognostic marker in patients with glioblastoma. PLoS ONE 12(6):e0178693

    Article  PubMed  PubMed Central  Google Scholar 

  88. Maher RL, Wallace SS, Pederson DS (2019) The lyase activity of bifunctional DNA glycosylases and the 3’-diesterase activity of APE1 contribute to the repair of oxidized bases in nucleosomes. Nucleic Acids Res 47(6):2922–2931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kuznetsova AA, Fedorova OS, Kuznetsov NA (2018) Kinetic features of 3’-5’ exonuclease activity of human AP-endonuclease APE1. Molecules 23(9):2101

    Article  PubMed Central  Google Scholar 

  90. Ma X et al (2019) Downregulation of APE1 potentiates breast cancer cells to olaparib by inhibiting PARP-1 expression. Breast Cancer Res Treat 176(1):109–117

    Article  CAS  PubMed  Google Scholar 

  91. Kladova OA et al (2020) Modulation of the apurinic/apyrimidinic endonuclease activity of human APE1 and of its natural polymorphic variants by base excision repair proteins. Int J Mol Sci 21(19):7147

    Article  CAS  PubMed Central  Google Scholar 

  92. Lin Y et al (2018) APE2 promotes DNA damage response pathway from a single-strand break. Nucleic Acids Res 46(5):2479–2494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Mengwasser KE et al (2019) Genetic screens reveal FEN1 and APEX2 as BRCA2 synthetic lethal targets. Mol Cell 73(5):885–899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gros L et al (2004) The major human AP endonuclease (Ape1) is involved in the nucleotide incision repair pathway. Nucleic Acids Res 32(1):73–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kuznetsova AA et al (2020) Effect of the substrate structure and metal ions on the hydrolysis of undamaged RNA by human AP endonuclease APE1. Acta Naturae 12(2):74–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Chohan M et al (2015) Human apurinic/apyrimidinic endonuclease 1 (APE1) has 3’ RNA phosphatase and 3’ exoribonuclease activities. J Mol Biol 427(2):298–311

    Article  CAS  PubMed  Google Scholar 

  97. Nassour H et al (2016) Peroxiredoxin 1 interacts with and blocks the redox factor APE1 from activating interleukin-8 expression. Sci Rep 6:29389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Tell G, Fantini D, Quadrifoglio F (2010) Understanding different functions of mammalian AP endonuclease (APE1) as a promising tool for cancer treatment. Cell Mol Life Sci 67(21):3589–3608

    Article  CAS  PubMed  Google Scholar 

  99. Vascotto C et al (2015) Functional regulation of the apurinic/apyrimidinic endonuclease 1 by nucleophosmin: impact on tumor biology. Oncogene 34(26):3482

    Article  CAS  PubMed  Google Scholar 

  100. Kabzinski J et al (2019) Sirt3 regulates the level of mitochondrial DNA repair activity through deacetylation of NEIL1, NEIL2, OGG1, MUTYH, APE1 and LIG3 in colorectal cancer. Pol Przegl Chir 92(1):1–4

    Article  PubMed  Google Scholar 

  101. Aeby E et al (2016) Peroxiredoxin 1 protects telomeres from oxidative damage and preserves telomeric DNA for extension by telomerase. Cell Rep 17(12):3107–3114

    Article  CAS  PubMed  Google Scholar 

  102. Zhou J et al (2017) NEIL3 repairs telomere damage during s phase to secure chromosome segregation at mitosis. Cell Rep 20(9):2044–2056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Shatilla A et al (2005) Identification of two apurinic/apyrimidinic endonucleases from Caenorhabditis elegans by cross-species complementation. DNA Repair (Amst) 4(6):655–670

    Article  CAS  Google Scholar 

  104. Sander M, Lowenhaupt K, Rich A (1991) Drosophila Rrp1 protein: an apurinic endonuclease with homologous recombination activities. Proc Natl Acad Sci USA 88(15):6780–6784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Graifer D, Karpova G (2020) Ribosomal protein uS3 in cell biology and human disease: Latest insights and prospects. BioEssays 42(12):e200124

    Article  Google Scholar 

  106. Ramotar D et al (1991) Cellular role of yeast Apn1 apurinic endonuclease/3’-diesterase: repair of oxidative and alkylation DNA damage and control of spontaneous mutation. Mol Cell Biol 11(9):4537–4544

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Johnson RE et al (1998) Identification of APN2, the Saccharomyces cerevisiae homolog of the major human AP endonuclease HAP1, and its role in the repair of abasic sites. Genes Dev 12(19):3137–3143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Beard WA (2020) DNA polymerase beta: Closing the gap between structure and function. DNA Repair (Amst) 93:102910

    Article  CAS  Google Scholar 

  109. Karimi-Busheri F et al (1998) Repair of DNA strand gaps and nicks containing 3’-phosphate and 5’-hydroxyl termini by purified mammalian enzymes. Nucleic Acids Res 26(19):4395–4400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Whitaker AM et al (2017) Base excision repair of oxidative DNA damage: from mechanism to disease. Front Biosci (Landmark Ed) 22:1493–1522

    Article  CAS  Google Scholar 

  111. Zhao S et al (2019) Mutation in DNA polymerase beta causes spontaneous chromosomal instability and inflammation-associated carcinogenesis in mice. Cancers (Basel) 11(8):1160

    Article  CAS  Google Scholar 

  112. Wang M et al (2020) DNA polymerase beta modulates cancer progression via enhancing CDH13 expression by promoter demethylation. Oncogene 39(33):5507–5519

    Article  CAS  PubMed  Google Scholar 

  113. Liu Y et al (2005) DNA polymerase beta and flap endonuclease 1 enzymatic specificities sustain DNA synthesis for long patch base excision repair. J Biol Chem 280(5):3665–3674

    Article  CAS  PubMed  Google Scholar 

  114. Woodrick J et al (2017) A new sub-pathway of long-patch base excision repair involving 5’ gap formation. EMBO J 36(11):1605–1622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Asagoshi K et al (2012) Single-nucleotide base excision repair DNA polymerase activity in C elegans in the absence of DNA polymerase beta. Nucleic Acids Res 40(2):670–681

    Article  CAS  PubMed  Google Scholar 

  116. Boehm EM, Gildenberg MS, Washington MT (2016) The Many roles of PCNA in eukaryotic DNA REPLICATION. Enzymes 39:231–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Volkova NV et al (2020) Mutational signatures are jointly shaped by DNA damage and repair. Nat Commun 11(1):2169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bebenek K et al (2005) Biochemical properties of Saccharomyces cerevisiae DNA polymerase IV. J Biol Chem 280(20):20051–20058

    Article  CAS  PubMed  Google Scholar 

  119. Jain R, Aggarwal AK, Rechkoblit O (2018) Eukaryotic DNA polymerases. Curr Opin Struct Biol 53:77–87

    Article  CAS  PubMed  Google Scholar 

  120. Gellon L et al (2008) Intrinsic 5’-deoxyribose-5-phosphate lyase activity in Saccharomyces cerevisiae Trf4 protein with a possible role in base excision DNA repair. DNA Repair (Amst) 7(2):187–198

    Article  CAS  Google Scholar 

  121. Daley JM, Wilson TE, Ramotar D (2010) Genetic interactions between HNT3/Aprataxin and RAD27/FEN1 suggest parallel pathways for 5’ end processing during base excision repair. DNA Repair (Amst) 9(6):690–699

    Article  CAS  Google Scholar 

  122. Sallmyr A et al (2020) Human DNA ligases in replication and repair. DNA Repair (Amst) 93:102908

    Article  CAS  Google Scholar 

  123. Williams JS et al (2021) High-fidelity DNA ligation enforces accurate Okazaki fragment maturation during DNA replication. Nat Commun 12(1):482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bauer RJ et al (2017) Comparative analysis of the end-joining activity of several DNA ligases. PLoS ONE 12(12):190062

    Article  Google Scholar 

  125. Pergolizzi G, Wagner GK, Bowater RP (2016) Biochemical and Structural characterisation of DNA ligases from bacteria and archaea. Biosci Rep 36(5):00391

    Article  PubMed  Google Scholar 

  126. Lu G et al (2016) Ligase I and ligase III mediate the DNA double-strand break ligation in alternative end-joining. Proc Natl Acad Sci U S A 113(5):1256–1260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kurosawa A, Kuboshima H, Adachi N (2020) Complex genetic interactions between DNA polymerase beta and the NHEJ ligase. FEBS J 287(2):377–385

    Article  CAS  PubMed  Google Scholar 

  128. Caglayan M, Wilson SH (2015) Oxidant and environmental toxicant-induced effects compromise DNA ligation during base excision DNA repair. DNA Repair (Amst) 35:85–89

    Article  CAS  Google Scholar 

  129. Ismail IH et al (2015) The RNF138 E3 ligase displaces Ku to promote DNA end resection and regulate DNA repair pathway choice. Nat Cell Biol 17(11):1446–1457

    Article  CAS  PubMed  Google Scholar 

  130. Horton JK et al (2018) XRCC1 phosphorylation affects aprataxin recruitment and DNA deadenylation activity. DNA Repair (Amst) 64:26–33

    Article  CAS  Google Scholar 

  131. Wilson DM 3rd et al (2017) Systematic analysis of DNA crosslink repair pathways during development and aging in Caenorhabditis elegans. Nucleic Acids Res 45(16):9467–9480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Gorski MM et al (2003) The Drosophila melanogaster DNA Ligase IV gene plays a crucial role in the repair of radiation-induced DNA double-strand breaks and acts synergistically with Rad54. Genetics 165(4):1929–1941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Donahue SL et al (2001) Mitochondrial DNA ligase function in Saccharomyces cerevisiae. Nucleic Acids Res 29(7):1582–1589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Arakawa H et al (2012) Functional redundancy between DNA ligases I and III in DNA replication in vertebrate cells. Nucleic Acids Res 40(6):2599–2610

    Article  CAS  PubMed  Google Scholar 

  135. Polo LM et al (2019) Efficient single-strand break repair requires binding to both poly(ADP-Ribose) and DNA by the central BRCT domain of XRCC1. Cell Rep 26(3):573–581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Reynolds P et al (2015) Disruption of PARP1 function inhibits base excision repair of a sub-set of DNA lesions. Nucleic Acids Res 43(8):4028–4038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Lavrik OI (2020) PARPs’ impact on base excision DNA repair. DNA Repair (Amst) 93:102911

    Article  CAS  Google Scholar 

  138. Wilk A et al (2020) Extracellular NAD(+) enhances PARP-dependent DNA repair capacity independently of CD73 activity. Sci Rep 10(1):651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Sukhanova M, Khodyreva S, Lavrik O (2010) Poly(ADP-ribose) polymerase 1 regulates activity of DNA polymerase beta in long patch base excision repair. Mutat Res 685(1–2):80–89

    Article  CAS  PubMed  Google Scholar 

  140. Hanzlikova H et al (2017) Overlapping roles for PARP1 and PARP2 in the recruitment of endogenous XRCC1 and PNKP into oxidized chromatin. Nucleic Acids Res 45(5):2546–2557

    CAS  PubMed  Google Scholar 

  141. Kutuzov MM et al (2021) The contribution of PARP1, PARP2 and poly(ADP-ribosyl)ation to base excision repair in the nucleosomal context. Sci Rep 11(1):4849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Mateu-Jimenez M et al (2016) Reduced tumor burden through increased oxidative stress in lung adenocarcinoma cells of PARP-1 and PARP-2 knockout mice. Biochimie 121:278–286

    Article  CAS  PubMed  Google Scholar 

  143. Abbotts R, Wilson DM 3rd (2017) Coordination of DNA single strand break repair. Free Radic Biol Med 107:228–244

    Article  CAS  PubMed  Google Scholar 

  144. Ray Chaudhuri A (2017) Nussenzweig A (2017) The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol 18(10):610–621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Velagapudi UK et al (2021) Recent development in the discovery of PARP inhibitors as anticancer agents: a patent update (2016–2020). Expert Opin Ther Pat 31:1–15

    Article  Google Scholar 

  146. Gelmon KA et al (2021) Clinical effectiveness of olaparib monotherapy in germline BRCA-mutated, HER2-negative metastatic breast cancer in a real-world setting: phase IIIb LUCY interim analysis. Eur J Cancer 152:68–77

    Article  CAS  PubMed  Google Scholar 

  147. Dequen F, Gagnon SN, Desnoyers S (2005) Ionizing radiations in Caenorhabditis elegans induce poly(ADP-ribosyl)ation, a conserved DNA-damage response essential for survival. DNA Repair (Amst) 4(7):814–825

    Article  CAS  Google Scholar 

  148. Crone B et al (2015) Elemental bioimaging of cisplatin in caenorhabditis elegans by LA-ICP-MS. Metallomics 7(7):1189–1195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Neumann C et al (2020) The role of poly(ADP-ribose) polymerases in manganese exposed Caenorhabditis elegans. J Trace Elem Med Biol 57:21–27

    Article  CAS  PubMed  Google Scholar 

  150. Boamah EK et al (2012) Poly(ADP-Ribose) polymerase 1 (PARP-1) regulates ribosomal biogenesis in Drosophila nucleoli. PLoS Genet 8(1):1002442

    Article  Google Scholar 

  151. Bordet G et al (2020) Poly(ADP-ribose) polymerase 1 in genome-wide expression control in Drosophila. Sci Rep 10(1):21151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Tao Z, Gao P, Liu HW (2009) Studies of the expression of human poly(ADP-ribose) polymerase-1 in Saccharomyces cerevisiae and identification of PARP-1 substrates by yeast proteome microarray screening. Biochemistry 48(49):11745–11754

    Article  CAS  PubMed  Google Scholar 

  153. Kirby TW et al (2015) Nuclear localization of the DNA repair scaffold XRCC1: uncovering the functional role of a bipartite NLS. Sci Rep 5:13405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Cannan WJ et al (2017) The human ligase IIIalpha-XRCC1 protein complex performs DNA nick repair after transient unwrapping of nucleosomal DNA. J Biol Chem 292(13):5227–5238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Vasil’eva IA, Moor NA, Lavrik OI (2020) Effect of human XRCC1 protein oxidation on the functional activity of its complexes with the key enzymes of DNA base excision repair. Biochemistry (Mosc) 85(3):288–299

    Article  CAS  Google Scholar 

  156. Xu C et al (2019) Deficiency of X-ray repair cross-complementing group 1 in primordial germ cells contributes to male infertility. FASEB J 33(6):7427–7436

    Article  CAS  PubMed  Google Scholar 

  157. Dutta D et al (2020) Effect of Arg399Gln single-nucleotide polymorphism in XRCC1 gene on survival rate of Indian squamous cell head-and-neck cancer patients. J Cancer Res Ther 16(3):551–558

    Article  CAS  PubMed  Google Scholar 

  158. Kaur J et al (2020) Association of XRCC1, XRCC2 and XRCC3 gene polymorphism with Esophageal cancer risk. Clin Exp Gastroenterol 13:73–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ghosh S et al (2015) Partial loss of the DNA repair scaffolding protein, Xrcc1, results in increased brain damage and reduced recovery from ischemic stroke in mice. Neurobiol Aging 36(7):2319–2330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Puerta-Garcia E et al (2020) Effect of DPYD, MTHFR, ABCB1, XRCC1, ERCC1 and GSTP1 on chemotherapy related toxicity in colorectal carcinoma. Surg Oncol 35:388–398

    Article  CAS  PubMed  Google Scholar 

  161. Soliman AHM et al (2020) Genetic polymorphisms in XRCC1, OGG1, and XRCC3 DNA repair genes and DNA damage in radiotherapy workers. Environ Sci Pollut Res Int 27(35):43786–43799

    Article  CAS  PubMed  Google Scholar 

  162. Fenech M et al (1991) Cloning and characterization of the rad4 gene of Schizosaccharomyces pombe; a gene showing short regions of sequence similarity to the human XRCC1 gene. Nucleic Acids Res 19(24):6737–6741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Marintchev A et al (2000) Domain specific interaction in the XRCC1-DNA polymerase beta complex. Nucleic Acids Res 28(10):2049–2059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Malfatti MC et al (2020) New perspectives in cancer biology from a study of canonical and non-canonical functions of base excision repair proteins with a focus on early steps. Mutagenesis 35(1):129–149

    Article  CAS  PubMed  Google Scholar 

  165. Sung H et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249

    Article  PubMed  Google Scholar 

  166. Ryu CS et al (2020) MPG and NPRL3 polymorphisms are associated with ischemic stroke susceptibility and post-stroke mortality. Diagnostics (Basel) 10(11):947

    Article  CAS  Google Scholar 

  167. de Barrios O et al (2019) ZEB1 promotes inflammation and progression towards inflammation-driven carcinoma through repression of the DNA repair glycosylase MPG in epithelial cells. Gut 68(12):2129–2141

    Article  PubMed  Google Scholar 

  168. Broderick P et al (2006) Evaluation of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes in familial colorectal cancer predisposition. BMC Cancer 6:243

    Article  PubMed  PubMed Central  Google Scholar 

  169. Ye F et al (2019) Association of SMUG1 SNPs in intron region and linkage disequilibrium with occurrence of cervical carcinoma and HPV infection in Chinese population. J Cancer 10(1):238–248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Jiang S et al. (2021) Associations of APE1 and OGG1 polymorphisms with onset and prognosis of bladder cancer. Panminerva Med

  171. Czarny P et al (2015) Association between single nucleotide polymorphisms of MUTYH, hOGG1 and NEIL1 genes, and depression. J Affect Disord 184:90–96

    Article  CAS  PubMed  Google Scholar 

  172. Sliwinski T et al (2009) Polymorphisms of the DNA base excision repair gene MUTYH in head and neck cancer. Exp Oncol 31(1):57–59

    CAS  PubMed  Google Scholar 

  173. Jensen KA, Shi X, Yan S (2020) Genomic alterations and abnormal expression of APE2 in multiple cancers. Sci Rep 10(1):3758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Wright G, Gassman NR (2020) Transcriptional dysregulation of base excision repair proteins in breast cancer. DNA Repair (Amst) 93:102922

    Article  CAS  Google Scholar 

  175. Simon H et al (2020) OGG1 deficiency alters the intestinal microbiome and increases intestinal inflammation in a mouse model. PLoS ONE 15(1):e0227501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Mohamed RH et al (2016) Association of XRCC1 and OGG1 DNA repair gene polymorphisms with rheumatoid arthritis in Egyptian patients. Gene 578(1):112–116

    Article  CAS  PubMed  Google Scholar 

  177. Kwiatkowski D et al (2015) Variants of base excision repair genes MUTYH, PARP1 and XRCC1 in Alzheimer’s disease risk. Neuropsychobiology 71(3):176–186

    Article  CAS  PubMed  Google Scholar 

  178. Imai K et al (2003) Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat Immunol 4(10):1023–1028

    Article  CAS  PubMed  Google Scholar 

  179. Zheng L et al (2007) Fen1 mutations result in autoimmunity, chronic inflammation and cancers. Nat Med 13(7):812–819

    Article  CAS  PubMed  Google Scholar 

  180. Zhu Y et al (2020) LINC00467 is up-regulated by TDG-mediated acetylation in non-small cell lung cancer and promotes tumor progression. Oncogene 39(38):6071–6084

    Article  CAS  PubMed  Google Scholar 

  181. Yan JB et al (2020) Insulin and metformin control cell proliferation by regulating TDG-mediated DNA demethylation in liver and breast cancer cells. Mol Ther Oncolytics 18:282–294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Li D et al (2020) The HOTAIRM1/miR-107/TDG axis regulates papillary thyroid cancer cell proliferation and invasion. Cell Death Dis 11(4):227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Tomkinson AE, Naila T, Khattri BS (2020) Altered DNA ligase activity in human disease. Mutagenesis 35(1):51–60

    Article  CAS  PubMed  Google Scholar 

  184. Ke Y et al (2019) The role of PARPs in inflammation-and metabolic-related diseases: molecular mechanisms and beyond. Cells 8(9):1047

    Article  CAS  PubMed Central  Google Scholar 

  185. Pazzaglia S, Pioli C (2019) Multifaceted role of PARP-1 in DNA repair and inflammation: pathological and therapeutic implications in cancer and non-cancer diseases. Cells 9(1):41

    Article  PubMed Central  Google Scholar 

  186. Li Q, Ma R, Zhang M (2018) XRCC1 rs1799782 (C194T) polymorphism correlated with tumor metastasis and molecular subtypes in breast cancer. Onco Targets Ther 11:8435–8444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Wu W et al (2021) Neuronal enhancers are hotspots for DNA single-strand break repair. Nature

  188. Yoon G, Caldecott KW (2018) Nonsyndromic cerebellar ataxias associated with disorders of DNA single-strand break repair. Handb Clin Neurol 155:105–115

    Article  PubMed  Google Scholar 

  189. Londero AP et al (2014) Expression and prognostic significance of APE1/Ref-1 and NPM1 proteins in high-grade ovarian serous cancer. Am J Clin Pathol 141(3):404–414

    Article  PubMed  Google Scholar 

  190. Meng L et al (2019) 2’,3’-dideoxycytidine, a DNA polymerase-beta inhibitor, reverses memory deficits in a mouse model of Alzheimer’s disease. J Alzheimers Dis 67(2):515–525

    Article  CAS  PubMed  Google Scholar 

  191. Wu Q et al (2020) Two polymorphic mutations in promoter region of DNA polymerase beta in relatively higher percentage of thymic hyperplasia patients. Thorac Cancer 12:588–592

    Article  PubMed  PubMed Central  Google Scholar 

  192. Murphy DL et al (2012) The E288K colon tumor variant of DNA polymerase beta is a sequence specific mutator. Biochemistry 51(26):5269–5275

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the College of Health and Life Sciences, Hamad Bin Khalifa University, for providing scholarships to both N.N.H and N.E. The schematic representations were created using Biorender.com.

Funding

Qatar Foundation to the College of Health and Life Sciences, Hamad Bin Khalifa University, Education City, Doha, Qatar.

Author information

Authors and Affiliations

  1. Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University, Education City, Doha, Qatar

    Nagham Nafiz Hindi, Noha Elsakrmy & Dindial Ramotar

Authors
  1. Nagham Nafiz Hindi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Noha Elsakrmy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dindial Ramotar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NNH, wrote the entire manuscript using a draft provided by NE; NNH, prepared the Tables and Figures and completed the reference list; DR, extensively revised the complete manuscript and both DR and NNH finalized the manuscript.

Corresponding author

Correspondence to Dindial Ramotar.

Ethics declarations

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

All authors gave their consent for publication.

Availability of data and material

Not applicable.

Conflict of interest

All the authors declared that there are no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hindi, N.N., Elsakrmy, N. & Ramotar, D. The base excision repair process: comparison between higher and lower eukaryotes. Cell. Mol. Life Sci. 78, 7943–7965 (2021). https://doi.org/10.1007/s00018-021-03990-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-021-03990-9

Keywords

Search

Navigation