DNA yanlış eşleşme onarımı ve erkek infertilitesi

Yanlış eşleşme onarımı, erkek germ hücrelerinin gelişimi sürecinde farklı tipteki DNA hasarlarının onarımında yer alırken, aynı zamanda mayo-tik rekombinasyonda da önemli görevler üstlenir. Hayvan modelleri ve insan çalışmaları ile MMR genlerindeki değişikliklerin ve ekspresyon hatalarının fertilite sorunlarına yol açabildiği bildirilmiştir. MMR genle-rinin bazıları için dizileme çalışmaları yapılmış ve bazı nonobstrüktif in-fertil erkeklerde gözlemlenen fenotipler hakkında daha fazla bilgi sağlan-mıştır. Bununla birlikte son yıllarda yapılan az sayıda çalışma MMR’daki epigenetik değişikliklerin erkek infertilitesiyle potansiyel ilişkisini ortaya koymuştur. Bu derlemede, spermatogenezde mayotik rekombinasyona ve onarım süreçlerine dahil olan MMR genleri ve proteinlerinin erkek fertilitesi üzerine etkisi ile ilgili mevcut bilgimiz özetlenerek, bu genler ve proteinlerdeki hataların erkek infertilitesi ile ilişkilerinin araştırıldığı güncel moleküler çalışmalara odaklanılmıştır.

DNA mismatch repair and male infertility

Mismatch repair is involved in the repair of different types of DNA damage during the development of male germ cells and also plays important roles in meiotic recombination. It has been reported in animal models and human studies that alterations in MMR genes and expression errors may lead to fertility problems. Sequencing studies have been performed for some of the MMR genes and more information has been provided about the phenotypes observed in some nonobstructive infertile men. However, few recent studies have revealed a potential relationship between epigenetic changes in MMR and male infertility. In this review, our current knowledge about the effects of MMR genes and proteins involved in meiotic recombination and repair processes in spermatogenesis on male fertility is summarized, and it is focused on recent molecular studies investigating the relationship of defects in these genes and proteins with male infertility.

___

  • 1.Zegers-Hochschild F, Adamson GD, J de Mouzon, Ishihara O, Mansour R, Nygren K, et al. International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology 2009. Fertil Steril 2009;92:1520–4. [CrossRef ]
  • 2.Choy JT, Eisenberg ML. Male infertility as a window to health. Fertil Steril 2018;110:810–4. [CrossRef ]
  • 3.Krausz C, Riera-Escamilla A. Genetics of male infertility. Nat Rev Urol 2018;15:369–84. [CrossRef ]
  • 4.Kuang W. The Initial Consultation for Male Infertility. In: Sabanegh J, editors. Male Infertility. Current Clinical Urology. Totowa, NJ: Humana Press; 2011. [CrossRef ]
  • 5.Hekim N, Gure MA, Mahmutoglu AM, Gunes S, Asci R, Henkel R. SNP’s in xenobiotic metabolism and male infertility. Xenobiotica 2020;50:363–70. [CrossRef ]
  • 6.Xie Y, Khan R, Wahab F, Hussain HMJ, Ali A, Ma H, et al. The testis-specifically expressed Dpep3 is not essential for male fertility in mice. Gene 2019;711:143925. [CrossRef ]
  • 7.Kuchakulla M, Narasimman M, Khodamoradi K, Khosravizadeh Z, Ramasamy R. How defective spermatogenesis affects sperm DNA integrity. Andrologia 2020;53:e13615. [CrossRef ]
  • 8.Gunes S, Esteves SC. Role of genetics and epigenetics in male infertility. Andrologia 2020;53:e13586. [CrossRef ]
  • 9.Carrell DT. Epigenetics of the male gamete. Fertil Steril 2012;97:267–74. [CrossRef ]
  • 10.Bjorndahl L, Kvist U. Structure of chromatin in spermatozoa. Adv Exp Med Biol 2014;791:1–11. [CrossRef]
  • 11. Bungum M. Role of sperm DNA integrity in fertility. In: Pereira LV, editor. Embryology –Updates and Highlights on Classic Topics. IntechOpen. 2012. [CrossRef ]
  • 12.Gunes S, Al-Sadaan M, Agarwal A. Spermatogenesis, DNA damage and DNA repair mechanisms in male infertility. Reprod Biomed Online 2015;31:309–19. [CrossRef ]
  • 13.Gunes S, Sertyel S. Sperm DNA Damage and Oocyte Repair Capability. In: Zini A, Agarwal A, editors. A Clinician’s Guide to Sperm DNA and Chromatin Damage. Cham: Springer International Publishing; 2018. p.321–46. [CrossRef ]
  • 14.Marchetti F, Wyrobek AJ. DNA repair decline during mouse spermiogenesis results in the accumulation of heritable DNA damage. DNA Repair (Amst) 2008;7:572–81. [CrossRef ]
  • 15.Aitken RJ, De Iuliis GN. On the possible origins of DNA damage in human spermatozoa. Mol Hum Reprod 2010;16:3–13. [CrossRef]
  • 16.Boushaba S, Belaaloui G. Sperm DNA fragmentation and standard semen parameters in algerian infertile male partners. World J Mens Health 2015;33:1–7. [CrossRef ]
  • 17.Erenpreiss J, Elzanaty S, Giwercman A. Sperm DNA damage in men from infertile couples. Asian J Androl 2008;10:786–90. [CrossRef ]
  • 18.Muratori M, Piomboni P, Baldi E, Filimberti E, Pecchioli P, Moretti E, et al. Functional and ultrastructural features of DNA-fragmented human sperm. J Androl 2000;21:903–12. https://onlinelibrary.wiley.com/doi/epdf/10.1002/j.1939-4640.2000.tb03421.x
  • 19.Wyrobek AJ, Eskenazi B, Young S, Arnheim N, Tiemann-Boege I, Jabs EW, et al. Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm. Proc Natl Acad Sci U S A 2006;103:9601–6. [CrossRef ]
  • 20.Simon L, Zini A, Dyachenko A, Ciampi A, Carrell DT. A systematic review and meta-analysis to determine the effect of sperm DNA damage on in vitro fertilization and intracytoplasmic sperm injection outcome. Asian J Androl 2017;19:80–90. [CrossRef ]
  • 21.Schulte RT, Ohl DA, Sigman M, Smith GD. Sperm DNA damage in male infertility: etiologies, assays, and outcomes. J Assist Reprod Genet 2010;27:3–12. [CrossRef ]
  • 22.Jung M, Wells D, Rusch J, Ahmad S, Marchini J, Myers SR, Conrad DF. Unified single-cell analysis of testis gene regulation and pathology in five mouse strains. eLife 2019;8. [CrossRef ]
  • 23.Krausz C, Riera-Escamilla A, Moreno-Mendoza D, Holleman K, Cioppi F, Algaba F, et al. Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men. Genet Med 2020;22:1956–66. [CrossRef ]
  • 24.Markandona O, Dafopoulos K, Anifandis G, Messini CI, Dimitraki M, Tsezou A, et al. Single-nucleotide polymorphism rs 175080 in the MLH3 gene and its relation to male infertility. J Assist Reprod Genet 2015;32:1795–9. [CrossRef ]
  • 25.Terribas E, Bonache S, Garcia-arevalo M, Sanchez J, Franco E, Bassas L, Larriba S. Changes in the expression profile of the meiosis-involved mismatch repair genes in impaired human spermatogenesis. J Androl 2010;31:346–57. [CrossRef ]
  • 26.Jiricny J. Postreplicative mismatch repair. Cold Spring Harb Perspect Biol 2013;5:a012633. [CrossRef ]
  • 27.Chatterjee N, Walker GC. Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen 2017;58:235–63. [CrossRef ]
  • 28.Li GM. Mechanisms and functions of DNA mismatch repair. Cell Res 2008;18:85–98. [CrossRef ]
  • 29.Manhart CM, Alani E. Roles for mismatch repair family proteins in promoting meiotic crossing over. DNA Repair (Amst) 2016;38:84–93. [CrossRef ]
  • 30.Peltomaki P. Update on Lynch syndrome genomics. Fam Cancer 2016;15:385–93. [CrossRef ]
  • 31.Modrich P. Mechanisms in eukaryotic mismatch repair. J Biol Chem 2006;281:30305–9. [CrossRef ]
  • 32.Kunkel TA, Erie DA. Eukaryotic Mismatch Repair in Relation to DNA Replication. Annu Rev Genet 2015;49:291–313. [CrossRef]
  • 33.Feitsma H, Leal MC, Moens PB, Cuppen E, Schulz RW. Mlh1 deficiency in zebrafish results in male sterility and aneuploid as well as triploid progeny in females. Genetics 2007;175:1561–9. [CrossRef ]
  • 34.Crouse GF. Non-canonical actions of mismatch repair. DNA Repair (Amst) 2016;38:102–9. [CrossRef ]
  • 35.Spies M, Fishel R. Mismatch repair during homologous and homeologous recombination. Cold Spring Harb Perspect Biol 2015;7:a022657. [CrossRef ]
  • 36.Cooper TJ, Crawford MR, Hunt LJ, Marsolier-Kergoat MC, Llorente B, Neale MJ. Mismatch repair impedes meiotic crossover interference. bioRxiv 2018. [CrossRef ]
  • 37.Sanderson ML, Hassold TJ, Carrell DT. Proteins involved in meiotic recombination: a role in male infertility? Syst Biol Reprod Med 2008;54:57–74. [CrossRef ]
  • 38.Neyton S, Lespinasse F, Moens PB, Paul R, Gaudray P, Paquis-Flucklinger V, Santucci-Darmanin S. Association between MSH4 (MutS homologue 4) and the DNA strand-exchange RAD51 and DMC1 proteins during mammalian meiosis. Mol Hum Reprod 2004;10:917–24. [CrossRef ]
  • 39.Codina-Pascual M, Oliver-Bonet M, Navarro J, Campillo M, García F, Egozcue S, et al. Synapsis and meiotic recombination analyses: MLH1 focus in the XY pair as an indicator. Hum Reprod 2005;20:2133–9. [CrossRef ]
  • 40.Fischer JM, Dudley S, Miller AJ, Liskay RM. An intact Pms2 ATPase domain is not essential for male fertility. DNA Repair (Amst) 2016;39:46–51. [CrossRef ]
  • 41.Kneitz B, Cohen PE, Avdievich E, Zhu L, MF Kane, Hou H Jr, et al. MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice. Genes Dev 2000;14:1085–97. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC316572/
  • 42.Lipkin SM, Moens PB, Wang V, Lenzi M, Shanmugarajah D, Gilgeous A, et al. Meiotic arrest and aneuploidy in MLH3-deficient mice. Nat Genet 2002;31:385–90. [CrossRef ]
  • 43.Chen S, Wang G, Zheng X, Ge S, Dai Y, Ping P, et al. Whole-exome sequencing of a large Chinese azoospermia and severe oligospermia cohort identifies novel infertility causative variants and genes. Hum Mol Genet 2020;29:2451–9. [CrossRef ]
  • 44.Paul C, Povey JE, Lawrence NJ, Selfridge J, Melton DW, Saunders PTK. Deletion of genes implicated in protecting the integrity of male germ cells has differential effects on the incidence of DNA breaks and germ cell loss. PLoS One 2007;2:e989. [CrossRef ]
  • 45.Nogues C, Fernández C, Rajmil O, Templado C. Baseline expression profile of meiotic-specific genes in healthy fertile males. Fertil Steril 2009;92:578–82. [CrossRef ]
  • 46.Gunes S, Agarwal A, Henkel R, Mahmutoglu AM, Sharma R, Esteves SC, et al. Association between promoter methylation of MLH1 and MSH2 and reactive oxygen species in oligozoospermic men-A pilot study. Andrologia 2018;50:e12903. [CrossRef ]
  • 47.Song WY, Meng H, Wang XG, Jin HX, Yao GD, Shi SL, et al. Reduced microRNA-188-3p expression contributes to apoptosis of spermatogenic cells in patients with azoospermia. Cell Prolif 2017;50:e12297. [CrossRef ]
  • 48.Ferras C, Fernandes S, Silva J, Barros A, Sousa M. Expression analysis of MLH3, MLH1, and MSH4 in maturation arrest. Reprod Sci 2012;19:587–96. [CrossRef ]
  • 49.Ferras C, Zhou X, Sousa M, Lindblom A, Barros A. DNA mismatch repair gene hMLH3 variants in meiotic arrest. Fertil Steril 2007;88:1681–4. [CrossRef ]
  • 50.Kadyrova LY, Gujar V, Burdett V, Modrich PL, Kadyrov FA. Human MutLgamma, the MLH1-MLH3 heterodimer, is an endonuclease that promotes DNA expansion. Proc Natl Acad Sci U S A 2020;117:3535–42. [CrossRef ]
  • 51.Ji G, Long Y, Zhou Y, Huang C, Gu A, Wang X. Common variants in mismatch repair genes associated with increased risk of sperm DNA damage and male infertility. BMC Med 2012;10:49. [CrossRef ]
  • 52.Martinez-Uruena N, Macías L, Pérez-Cabornero L, Infante M, Lastra E, Cruz JJ, et al. Incidence of -93 MLH1 promoter polymorphism in familial and sporadic colorectal cancer. Colorectal Dis 2013;15:e118–23. [CrossRef ]
  • 53.Liu Y, Zhang X, Jia J, Tang L, Gao X, Yan L, et al. Correlation between polymorphisms in DNA mismatch repair genes and the risk of primary hepatocellular carcinoma for the Han population in northern China. Scand J Gastroenterol 2015;50:1404–10. [CrossRef ]
  • 54. Zhang X, Ding M, Ding X, Li T, Chen H. Six polymorphisms in genes involved in DNA double-strand break repair and chromosome synapsis: association with male infertility. Syst Biol Reprod Med 2015;61:187–93. [CrossRef ]
  • 55.Zhao X, Mu C, Ma J, Dai X, Jiao H. The association of four SNPs in DNA mismatch repair genes with idiopathic male infertility in northwest China. Int J Immunogenet 2019;46:451–8. [CrossRef ]
  • 56.Xu K, Lu T, Zhou H, Bai L, Xiang Y. The role of MSH5 C85T and MLH3 C2531T polymorphisms in the risk of male infertility with azoospermia or severe oligozoospermia. Clin Chim Acta 2010;411:49–52. [CrossRef ]
  • 57.Anifandis G, Markandona O, Dafopoulos K, Messini C, Tsezou A, Dimitraki M, et al. Embryological Results of Couples Undergoing ICSI-ET Treatments with Males Carrying the Single Nucleotide Polymorphism rs175080 of the MLH3 Gene. Int J Mol Sci 2017;18:314. [CrossRef ]
  • 58.Richardson LL, Pedigo C, Handel MA. Expression of deoxyribonucleic acid repair enzymes during spermatogenesis in mice. Biol Reprod 2000;62:789–96. [CrossRef ]
  • 59.Kolas NK, Svetlanov A, Lenzi ML, Macaluso FP, Lipkin SM, Liskay RM, et al. Localization of MMR proteins on meiotic chromosomes in mice indicates distinct functions during prophase I. J Cell Biol 2005;171:447–58. [CrossRef ]
  • 60.Miao HK, Chen LP, Cai DP, Kong WJ, Xiao L, Lin J. MSH3 rs26279 polymorphism increases cancer risk: a meta-analysis. Int J Clin Exp Pathol 2015;8:11060–7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637639/
  • 61. Morales F, Vásquez M, Santamaría C, Cuenca P, Corrales E, Monckton DG. A polymorphism in the MSH3 mismatch repair gene is associated with the levels of somatic instability of the expanded CTG repeat in the blood DNA of myotonic dystrophy type 1 patients. DNA Repair (Amst) 2016;40:57–66. [CrossRef ]
  • 62.Singh V, Jaiswal D, Singh K, Trivedi S, Agrawal NK, Gupta G, et al. Azoospermic infertility is associated with altered expression of DNA repair genes. DNA Repair (Amst) 2019;75:39–47. [CrossRef ]
  • 63.Hekim N, Gunes S, Asci R, Henkel R, Abur U. Semiquantitative promoter methylation of MLH1 and MSH2 genes and their impact on sperm DNA fragmentation and chromatin condensation in infertile men. Andrologia 2020;53:e13827. [CrossRef ]
Androloji Bülteni-Cover
  • ISSN: 2587-2524
  • Yayın Aralığı: Yılda 4 Sayı
  • Başlangıç: 1999
  • Yayıncı: Turgay Arık