Mikrobiol. Z. 2022; 84(1):72-79.
doi: https://doi.org/10.15407/microbiolj84.01.065

DNA Repair Enzymes as Therapeutic Agents: a Review

S.B. Dahikar, S.A. Bhutada

Sanjivani Arts, Commerce and Science College
Kopargaon, 423603, India

DNA damage is long recognized factor for development and progression of cancer in humans. Genome instability is the leading factor behind development of cancer. There are some DNA repair pathways and DNA damage checkpoints present in all creatures, without them the functional stability gets compromised.  Impaired DNA repair results in genomic instability leading to development of cancer, limited lifespan, early ageing. UV rays and Ionizing radiations are the major exogenous forces responsible for DNA damage, causing lesions in DNA. These lesions are cause of photoageing. Protection administered by conventional sunscreen is merely prophylactic if lesions have already occurred. There is an increasing demand for such product which can reverse or delay the effects of photoageing thus the protection offered by conventional sunscreen can be improved. This review focuses on recent developments on involvement of various DNA repair enzymes in treatment of cancer as well as in skincare products such as sunscreen.

Keywords: DNA damage, genome instability, DNA repair pathways, cancer, photoageing, sunscreen.

Full text

  1. Chatterjee N, Walker GC. Mechanisms of DNA damage, repair and mutagenesis. Environ Mol Mutagen. 2017; 58(5):235–263. https://doi.org/10.1002/em.22087
  2. Fleck O, Neilson O. DNA repair. Journal of Cell Science. 2004; 117:515–517. https://doi.org/10.1242/jcs.00952
  3. Antoniou AC, Wang X, Fredericksen ZS. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet. 2010; 42(10):885–892. https://doi.org/10.1038/ng.669
  4. Stahl W, Heinrich U, Aust O, Tronnier H, Sies H. Lycopene-rich products and dietary photoprotection. Photochem Photobiol Sci. 2006; 5(2):238–242. https://doi.org/10.1039/B505312A
  5. Megna M, Lembo S, Balato N, Monfrecola G. “Active” photoprotection: sunscreens with DNA repair enzymes. G Ital Dermatol Venereol. 2017; 152(3):302–307. https://doi.org/10.23736/S0392-0488.17.05567-5
  6. O’Driscoll M, Jeggo PA. The role of doublestrand break repair—insights from human genetics. Nat Rev Genet. 2006; 7:45–54. https://doi.org/10.1038/nrg1746
  7. Subba Rao K. Mechanisms of disease: DNA repair defects and neurological disease. Nat Clin Pract Neurol. 2007; 3:162–172. https://doi.org/10.1038/ncpneuro0448
  8. Thoms KM, Kuschal C, Emmert S. Lessons learned from DNA repair defective syndromes. Exp Dermatol. 2007; 16:532–544. https://doi.org/10.1111/j.1600-0625.2007.00559.x
  9. Terradas M, Martín M, Tusell L, Genescà A. Genetic activities in micronuclei: is the DNA entrapped in micronuclei lost for the cell? Mutat Res. 2010; 705(1):60–67. https://doi.org/10.1016/j.mrrev.2010.03.004
  10. Mishima M. Chromosomal aberrations, clastogens vs aneugens. Front Biosci (Schol Ed). 2017; 9(1):1–16. https://doi.org/10.2741/s468
  11. Giam M, Rancati G. Aneuploidy and chromosomal instability in cancer: a jackpot to chaos. Cell Div. 2015; 10:3. https://doi.org/10.1186/s13008-015-0009-7
  12. Ichijima Y, Yoshioka K, Yoshioka Y. DNA lesions induced by replication stress trigger mitotic aberration and tetraploidy development. PLoS One. 2010; 5(1):e8821. https://doi.org/10.1371/journal.pone.0008821
  13. Gregory CD, Milner AE. Regulation of cell survival in Burkitt lymphoma: implications from studies of apoptosis following cold-shock treatment. Int J Cancer. 1994; 57(3):419–426. https://doi.org/10.1002/ijc.2910570321
  14. Gafter-Gvili A, Zingerman B, Rozen-Zvi B, Ori Y, Green H, Lubin I, Malachi T, Gafter U, HermanEdelstein M. Oxidative stress-induced DNA damage and repair in human peripheral blood mononuclear cells: protective role of hemoglobin. PLoS One. 2013; 8(7):e68341. https://doi.org/10.1371/journal.pone.0068341
  15. Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell. 2010; 40:179–204. https://doi.org/10.1016/j.molcel.2010.09.019
  16. Tanaka K, Okada Y, Sekiguchi M. Restoration of ultraviolet-induced unscheduled DNA synthesis of xeroderma pigmentosum cells by insertion of T4 endonuclease V utilizing HVJ. PNE. 1976; 21(7):525–535.
  17. Lehman IR. DNA ligase: structure, mechanism, and function. Science. 1974; 186(4166):790–797. https://doi.org/10.1126/science.186.4166.790
  18. Zimmerman SB, Little JW, Oshinsky CK, Gellert M. Enzymatic joining of DNA strands: a novel reaction of diphosphopyridine nucleotide. Proceedings of the National Academy of Sciences of the United States of America. 1967; 57(6):1841. https://doi.org/10.1073/pnas.57.6.1841
  19. Engler MJ, Richardson CC. 1 DNA Ligases. In: The enzymes. Academic Press. 1982; 15:3–29. https://doi.org/10.1016/S1874-6047(08)60273-5
  20. Sadowski P, Ginsberg B, Yudelevich A, Feiner L, Hurwitz J. Enzymatic mechanisms of the repair and breakage of DNA. Cold Spring Harbor symposia on quantitative biology. Cold Spring Harbor Laboratory Press; v. 33. 1968. https://doi.org/10.1101/SQB.1968.033.01.020
  21. Tomkinson AE, Howes TRL, Wiest NE. DNA ligases as therapeutic targets. Transl Cancer Res. 2013; 2(3):1–17.
  22. Kuraoka I. Diversity of endonuclease V: from DNA repair to RNA editing. Biomolecules. 2015; 5(4):2194–2206. https://doi.org/10.3390/biom5042194
  23. Shiota S, Nakayama H. UV endonuclease of Micrococcus luteus, a cyclobutane pyrimidine dimer-DNA glycosylase/abasic lyase: Cloning and characterization of the gene. Proc Natl Acad Sci. 1997; 94(2):593–598. https://doi.org/10.1073/pnas.94.2.593
  24. Sancar A. Mechanisms of DNA Repair by Photolyase and Excision Nuclease (Nobel Lecture). Angew Chem, Int Ed Engl. 2016; 55:8502–8527. https://doi.org/10.1002/anie.201601524
  25. Dong KK, Damaghi N, Picart SD. UV-induced DNA damage initiates release of MMP-1 in human skin. Exp Dermatol. 2008; 17(12):1037–1044. https://doi.org/10.1111/j.1600-0625.2008.00747.x
  26. Kulms D, Zeise E, Pöppelmann B, Schwarz T. DNA damage, death receptor activation and reactive oxygen species contribute to ultraviolet radiation-induced apoptosis in an essential and independent way. Oncogene. 2002; 21(38):5844–5851. https://doi.org/10.1038/sj.onc.1205743
  27. Liu Z, Wang L, Zhong D. Dynamics and mechanisms of DNA repair by photolyase. Phys Chem Chem Phys. 2015; 17(18):11933–11949. https://doi.org/10.1039/C4CP05286B
  28. Stege H, Roza L, Vink AA. Enzyme plus light therapy to repair DNA damage in ultraviolet-Birradiated human skin. Proc Natl Acad Sci. 2000; 97(4):1790–1795. https://doi.org/10.1073/pnas.030528897
  29. Yarosh D, Klein J, O’Connor A, Hawk J, Rafal E, Wolf P. Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study. Xeroderma Pigmentosum Study Group. Lancet. 2001; 357(9260):926–929. https://doi.org/10.1016/S0140-6736(00)04214-8
  30. Ke MS, Camouse MM, Swain FR, UV protective effects of DNA repair enzymes and RNA lotion. Photochem Photobiol. 2008; 84(1):180–184.
  31. Berardesca E, Bertona M, Altabas K, Altabas V, Emanuele E. Reduced ultraviolet-induced DNA damage and apoptosis in human skin with topical application of a photolyase-containing DNA repair enzyme cream: clues to skin cancer prevention. Mol Med Rept. 2012; 5(2):570–574.
  32. Emanuele E, Altabas V, Altabas K, Berardesca E. Topical application of preparations containing DNA repair enzymes prevents ultravioletinduced telomere shortening and c-FOS proto-oncogene hyperexpression in human skin: An experimental pilot study. J Drugs Dermatol. 2013; 12:1017–1021.
  33. Gilchrest BA. Photoaging. J Invest Dermatol. 2013; 133(E1):E2-E6. https://doi.org/10.1038/skinbio.2013.176
  34. Grether-Beck S, Wlaschek M, Krutmann J, Scharffetter-Kochanek K. Photoschadigung und Photoalterung – Pravention und Behandlung. Photodamage and photoaging  – prevention and treatment. J der Dtsch Dermatologischen Gesellschaft. 2005; 3(s2):S19-S25. https://doi.org/10.1111/j.1610-0387.2005.04394.x
  35. Scharffetter-Kochanek K, Brenneisen P, Wenk J. Photoaging of the skin from phenotype to mechanisms. Exp Gerontol. 2000; 35(3):307–316. https://doi.org/10.1016/S0531-5565(00)00098-X
  36. Emanuele E. Reduced ultraviolet-induced DNA damage and apoptosis in human skin with topical application of a photolyase-containing DNA repair enzyme cream: Clues to skin cancer prevention. Mol Med Rep. 2012; 5(2):570–574. https://doi.org/10.3892/mmr.2011.673
  37. Doherty R, Madhusudan S. DNA Repair Endonucleases: Physiological Roles and Potential as Drug Targets. J Biomol Screen. 2015; 20(7):829–841. https://doi.org/10.1177/1087057115581581
  38. Leccia M-T, Lebbe C, Claudel J-P, Narda M, Basset-Seguin N. New Vision in Photoprotection and Photorepair. Dermatol Ther (Heidelb). 2019; 9(1):103–115. https://doi.org/10.1007/s13555-019-0282-5
  39. Zhang M, Wang L, Zhong D. Photolyase: Dynamics and electron-transfer mechanisms of DNA repair. Arch Biochem Biophys. 2017; 632:158–174. https://doi.org/10.1016/j.abb.2017.08.007
  40. Wolf P, Müllegger RR, Peter Soyer H. Topical Treatment with Liposomes Containing T4 Endonuclease V Protects Human Skin in vivo from Ultraviolet-Induced Upregulation of Interleukin-10 and Tumor Necrosis Factor-α. J Invest Dermatol. 2000; 114(1):149–156. https://doi.org/10.1046/j.1523-1747.2000.00839.x
  41. Puviani M, Barcella A, Milani M. Efficacy of a photolyase-based device in the treatment of cancerization field in patients with actinic  keratosis and non-melanoma skin cancer. G Ital Dermatol Venereol. 2013; 148(6):693–698.
  42. Krutmann J, Hansen PM. Algenenzym Photolyase  verbessert Schutz vor UVB-Schäden. Pharm Ztg. 2004; 149(20):50–53.
  43. Yarosh DB, Rosenthal A, Moy R. Six critical questions for DNA repair enzymes in skincare products: a review in dialog. Clin Cosmet Investig Dermatol. 2019; 12:617–624. https://doi.org/10.2147/CCID.S220741