Full Text:   <1961>

Summary:  <1681>

CLC number: R711.6

On-line Access: 2016-11-11

Received: 2016-06-28

Revision Accepted: 2016-09-17

Crosschecked: 2015-12-16

Cited: 3

Clicked: 3556

Citations:  Bibtex RefMan EndNote GB/T7714


Min-hao Hu


-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2016 Vol.17 No.1 P.10-20


Impact of DNA mismatch repair system alterations on human fertility and related treatments

Author(s):  Min-hao HU, Shu-yuan LIU, Ning WANG, Yan WU, Fan JIN

Affiliation(s):  Key Laboratory of Reproductive Genetics (Zhejiang), Ministry of Education, and Centre of Reproductive Medicine, Womens Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China

Corresponding email(s):   jinfan@zju.edu.cn

Key Words:  DNA mismatch repair, Infertility, Assisted reproductive technology

Min-hao HU, Shu-yuan LIU, Ning WANG, Yan WU, Fan JIN. Impact of DNA mismatch repair system alterations on human fertility and related treatments[J]. Journal of Zhejiang University Science B, 2016, 17(1): 10-20.

@article{title="Impact of DNA mismatch repair system alterations on human fertility and related treatments",
author="Min-hao HU, Shu-yuan LIU, Ning WANG, Yan WU, Fan JIN",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Impact of DNA mismatch repair system alterations on human fertility and related treatments
%A Min-hao HU
%A Shu-yuan LIU
%A Ning WANG
%A Yan WU
%A Fan JIN
%J Journal of Zhejiang University SCIENCE B
%V 17
%N 1
%P 10-20
%@ 1673-1581
%D 2016
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1500162

T1 - Impact of DNA mismatch repair system alterations on human fertility and related treatments
A1 - Min-hao HU
A1 - Shu-yuan LIU
A1 - Ning WANG
A1 - Yan WU
A1 - Fan JIN
J0 - Journal of Zhejiang University Science B
VL - 17
IS - 1
SP - 10
EP - 20
%@ 1673-1581
Y1 - 2016
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1500162

DNA mismatch repair (MMR) is one of the biological pathways, which plays a critical role in DNA homeostasis, primarily by repairing base-pair mismatches and insertion/deletion loops that occur during DNA replication. MMR also takes part in other metabolic pathways and regulates cell cycle arrest. Defects in MMR are associated with genomic instability, predisposition to certain types of cancers and resistance to certain therapeutic drugs. Moreover, genetic and epigenetic alterations in the MMR system demonstrate a significant relationship with human fertility and related treatments, which helps us to understand the etiology and susceptibility of human infertility. Alterations in the MMR system may also influence the health of offspring conceived by assisted reproductive technology in humans. However, further studies are needed to explore the specific mechanisms by which the MMR system may affect human infertility. This review addresses the physiological mechanisms of the MMR system and associations between alterations of the MMR system and human fertility and related treatments, and potential effects on the next generation.


关 键 词:DNA错配修复;不孕;辅助生殖技术;后代


Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Baker, S.M., Bronner, C.E., Zhang, L., et al., 1995. Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis. Cell, 82(2):309-319.

[2]Baker, S.M., Plug, A.W., Prolla, T.A., et al., 1996. Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over. Nat. Genet., 13(3):336-342.

[3]Bianchi, N.O., Richard, S.M., Peltomaki, P., et al., 2002. Mosaic AZF deletions and susceptibility to testicular tumors. Mutat. Res., 503(1-2):51-62.

[4]Brown, K.D., Rathi, A., Kamath, R., et al., 2003. The mismatch repair system is required for S-phase checkpoint activation. Nat. Genet., 33(1):80-84.

[5]Cannavo, E., Gerrits, B., Marra, G., et al., 2007. Characterization of the interactome of the human MutL homologues MLH1, PMS1, and PMS2. J. Biol. Chem., 282(5):2976-2986.

[6]Chen, J., Sadowski, I., 2005. Identification of the mismatch repair genes PMS2 and MLH1 as p53 target genes by using serial analysis of binding elements. PNAS, 102(13):4813-4818.

[7]Dada, R., Kumar, M., Jesudasan, R., et al., 2012. Epigenetics and its role in male infertility. J. Assist. Reprod. Genet., 29(3):213-223.

[8]de Ligt, J., Willemsen, M.H., van Bon, B.W., et al., 2012. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med., 367(20):1921-1929.

[9]de Vries, S.S., Baart, E.B., Dekker, M., et al., 1999. Mouse MutS-like protein Msh5 is required for proper chromosome synapsis in male and female meiosis. Genes. Dev., 13(5):523-531.

[10]Diaz-Padilla, I., Romero, N., Amir, E., et al., 2013. Mismatch repair status and clinical outcome in endometrial cancer: a systematic review and meta-analysis. Crit. Rev. Oncol. Hematol., 88(1):154-167.

[11]Edelmann, W., Cohen, P.E., Kneitz, B., et al., 1999. Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. Nat. Genet., 21(1):123-127.

[12]Feng, C., Wang, L., Dong, M., et al., 2008. Assisted reproductive technology may increase clinical mutation detection in male offspring. Fertil. Steril., 90(1):92-96.

[13]Ferras, C., Zhou, X.L., Sousa, M., et al., 2007. DNA mismatch repair gene hMLH3 variants in meiotic arrest. Fertil. Steril., 88(6):1681-1684.

[14]Ferras, C., Fernandes, S., Silva, J., et al., 2012. Expression analysis of MLH3, MLH1, and MSH4 in maturation arrest. Reprod. Sci., 19(6):587-596.

[15]Frazer, K.A., Murray, S.S., Schork, N.J., et al., 2009. Human genetic variation and its contribution to complex traits. Nat. Rev. Genet., 10(4):241-251.

[16]Garg, K., Shih, K., Barakat, R., et al., 2009. Endometrial carcinomas in women aged 40 years and younger: tumors associated with loss of DNA mismatch repair proteins comprise a distinct clinicopathologic subset. Am. J. Surg. Pathol., 33(12):1869-1877.

[17]Gnoth, C., Godehardt, E., Frank-Herrmann, P., et al., 2005. Definition and prevalence of subfertility and infertility. Hum. Reprod., 20(5):1144-1147.

[18]Guerrette, S., Acharya, S., Fishel, R., 1999. The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer. J. Biol. Chem., 274(10):6336-6341.

[19]Gunes, S., Al-Sadaan, M., Agarwal, A., 2015. Spermatogenesis, DNA damage and DNA repair mechanisms in male infertility. Reprod. BioMed. Online, 31(3):309-319.

[20]Guo, G., Wang, W., Bradley, A., 2004. Mismatch repair genes identified using genetic screens in Blm-deficient embryonic stem cells. Nature, 429(6994):891-895.

[21]Halabi, A., Ditch, S., Wang, J., et al., 2012. DNA mismatch repair complex MutSβ promotes GAA·TTC repeat expansion in human cells. J. Biol. Chem., 287(35):29958-29967.

[22]Halliday, J.L., Ukoumunne, O.C., Baker, H.W., et al., 2010. Increased risk of blastogenesis birth defects, arising in the first 4 weeks of pregnancy, after assisted reproductive technologies. Hum. Reprod., 25(1):59-65.

[23]Her, C., Zhao, N., Wu, X., et al., 2007. MutS homologues hMSH4 and hMSH5: diverse functional implications in humans. Front. Biosci., 12(1):905-911.

[24]Hienonen, T., Laiho, P., Salovaara, R., et al., 2003. Little evidence for involvement of MLH3 in colorectal cancer predisposition. Int. J. Cancer., 106(2):292-296.

[25]Iyer, R.R., Pluciennik, A., Burdett, V., et al., 2006. DNA mismatch repair: functions and mechanisms. Chem. Rev., 106(2):302-323.

[26]Jascur, T., Boland, C.R., 2006. Structure and function of the components of the human DNA mismatch repair system. Int. J. Cancer., 119(9):2030-2035.

[27]Ji, G., Long, Y., Zhou, Y., et al., 2012. Common variants in mismatch repair genes associated with increased risk of sperm DNA damage and male infertility. BMC Med., 10(1):49.

[28]Jiricny, J., 2006. The multifaceted mismatch-repair system. Nat. Rev. Mol. Cell. Biol., 7(5):335-346.

[29]Joehlin-Price, A.S., Perrino, C.M., Stephens, J., et al., 2014. Mismatch repair protein expression in 1049 endometrial carcinomas, associations with body mass index, and other clinicopathologic variables. Gynecol. Oncol., 133(1):43-47.

[30]Kang, S., Li, Y., Li, B., et al., 2014. Genetic variation of the E-cadherin gene is associated with primary infertility in patients with ovarian endometriosis. Fertil. Steril., 102(4):1149-1154.

[31]Karamurzin, Y., Zeng, Z., Stadler, Z.K., et al., 2012. Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature. Hum. Pathol., 43(10):1677-1687.

[32]Kim, M., Trinh, B.N., Long, T.I., et al., 2004. Dnmt1 deficiency leads to enhanced microsatellite instability in mouse embryonic stem cells. Nucleic Acids Res., 32(19):5742-5749.

[33]Kneitz, B., Cohen, P.E., Avdievich, E., et al., 2000. MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice. Genes Dev., 14(9):1085-1097.

[34]Kochanski, A., Merritt, T.A., Gadzinowski, J., et al., 2013. The impact of assisted reproductive technologies on the genome and epigenome of the newborn. J. Neonatal. Perinatal. Med., 6(2):101-108.

[35]Kolodner, R.D., Marsischky, G.T., 1999. Eukaryotic DNA mismatch repair. Curr. Opin. Genet. Dev., 9(1):89-96.

[36]Kondo, E., Horii, A., Fukushige, S., 2001. The interacting domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2. Nucleic Acids. Res., 29(8):1695-1702.

[37]Korhonen, M.K., Raevaara, T.E., Lohi, H., et al., 2007. Conditional nuclear localization of hMLH3 suggests a minor activity in mismatch repair and supports its role as a low-risk gene in HNPCC. Oncol. Rep., 17(2):351-354.

[38]Kunkel, T.A., Erie, D.A., 2005. DNA mismatch repair. Annu. Rev. Biochem., 74(1):681-710.

[39]Kurinczuk, J.J., Hansen, M., Bower, C., 2004. The risk of birth defects in children born after assisted reproductive technologies. Curr. Opin. Obstet. Gynecol., 16(3):201-209.

[40]Lahue, R.S., Au, K.G., Modrich, P., 1989. DNA mismatch correction in a defined system. Science, 245(4914):160-164.

[41]Li, G.M., 2008. Mechanisms and functions of DNA mismatch repair. Cell Res., 18(1):85-98.

[42]Lin, Y., Wilson, J.H., 2009. Diverse effects of individual mismatch repair components on transcription-induced CAG repeat instability in human cells. DNA Repair (Amst), 8(8):878-885.

[43]Lipkin, S.M., Wang, V., Jacoby, R., et al., 2000. MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability. Nat. Genet., 24(1):27-35.

[44]Lipkin, S.M., Moens, P.B., Wang, V., et al., 2002. Meiotic arrest and aneuploidy in MLH3-deficient mice. Nat. Genet., 31(4):385-390.

[45]Liu, H.X., Zhou, X.L., Liu, T., et al., 2003. The role of hMLH3 in familial colorectal cancer. Cancer. Res., 63(8):1894-1899.

[46]Lucifero, D., Mann, M.R., Bartolomei, M.S., et al., 2004. Gene-specific timing and epigenetic memory in oocyte imprinting. Hum. Mol. Genet., 13(8):839-849.

[47]Maduro, M.R., Casella, R., Kim, E., et al., 2003. Microsatellite instability and defects in mismatch repair proteins: a new aetiology for Sertoli cell-only syndrome. Mol. Hum. Reprod., 9(2):61-68.

[48]Maher, E.R., Afnan, M., Barratt, C.L., 2003. Epigenetic risks related to assisted reproductive technologies: epigenetics, imprinting, ART and icebergs? Hum. Reprod., 18(12):2508-2511.

[49]Mandon-Pepin, B., Touraine, P., Kuttenn, F., et al., 2008. Genetic investigation of four meiotic genes in women with premature ovarian failure. Eur. J. Endocrinol., 158(1):107-115.

[50]Manolio, T.A., Collins, F.S., Cox, N.J., et al., 2009. Finding the missing heritability of complex diseases. Nature, 461(7265):747-753.

[51]Marcon, E., Moens, P., 2003. MLH1p and MLH3p localize to precociously induced chiasmata of okadaic-acid-treated mouse spermatocytes. Genetics, 165(4):2283-2287.]

[52]Martins, A.D., Moreira, A.C., Sa, R., et al., 2015. Leptin modulates human Sertoli cells acetate production and glycolytic profile: a novel mechanism of obesity-induced male infertility? Biochim. Biophys. Acta, 1852(9):1824-1832.

[53]Modrich, P., 1991. Mechanisms and biological effects of mismatch repair. Annu. Rev. Genet., 25(1):229-253.

[54]Mukherjee, S., Ridgeway, A.D., Lamb, D.J., 2010. DNA mismatch repair and infertility. Curr. Opin. Urol., 20(6):525-532.

[55]Muraki, Y., Banno, K., Yanokura, M., et al., 2009. Epigenetic DNA hypermethylation: clinical applications in endometrial cancer (Review). Oncol. Rep., 22(5):967-972.

[56]Ni, B., Ma, H., Lin, Y., et al., 2014. Genetic variants in Ser-Arg protein-coding genes are associated with the risk of nonobstructive azoospermia in Chinese men. Fertil. Steril., 101(6):1711-1717.

[57]Niemitz, E.L., Feinberg, A.P., 2004. Epigenetics and assisted reproductive technology: a call for investigation. Am. J. Hum. Genet., 74(4):599-609.

[58]Oliveira, P.F., Martins, A.D., Moreira, A.C., et al., 2015. The Warburg effect revisited—lesson from the Sertoli cell. Med. Res. Rev., 35(1):126-151.

[59]Park, J.Y., Seong, S.J., Kim, T.J., et al., 2013. Pregnancy outcomes after fertility-sparing management in young women with early endometrial cancer. Obstet. Gynecol., 121(1):136-142.

[60]Pashaiefar, H., Sheikhha, M.H., Kalantar, S.M., et al., 2013. Analysis of MLH3 C2531T polymorphism in Iranian women with unexplained infertility. Iran. J. Reprod. Med., 11(1):19-24.

[61]Peltomaki, P., 2003. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J. Clin. Oncol., 21(6):1174-1179.

[62]Perry, J.R., Hsu, Y.H., Chasman, D.I., et al., 2014. DNA mismatch repair gene MSH6 implicated in determining age at natural menopause. Hum. Mol. Genet., 23(9):2490-2497.

[63]Pluciennik, A., Burdett, V., Baitinger, C., et al., 2013. Extrahelical (CAG)/(CTG) triplet repeat elements support proliferating cell nuclear antigen loading and MutLα endonuclease activation. PNAS, 110(30):12277-12282.

[64]Richardson, M.E., Bleiziffer, A., Tuttelmann, F., et al., 2014. Epigenetic regulation of the RHOX homeobox gene cluster and its association with human male infertility. Hum. Mol. Genet., 23(1):12-23.

[65]Santucci-Darmanin, S., Neyton, S., Lespinasse, F., et al., 2002. The DNA mismatch-repair MLH3 protein interacts with MSH4 in meiotic cells, supporting a role for this MutL homolog in mammalian meiotic recombination. Hum. Mol. Genet., 11(15):1697-1706.

[66]Serebrovska, Z.A., Serebrovskaya, T.V., Pyle, R.L., et al., 2006. Transmission of male infertility and intracytoplasmic sperm injection (mini-review). Fiziol. Zh., 52(3):110-118.

[67]Shih, K.K., Garg, K., Levine, D.A., et al., 2011. Clinicopathologic significance of DNA mismatch repair protein defects and endometrial cancer in women 40 years of age and younger. Gynecol. Oncol., 123(1):88-94.

[68]Shimodaira, H., Yoshioka-Yamashita, A., Kolodner, R.D., et al., 2003. Interaction of mismatch repair protein PMS2 and the p53-related transcription factor p73 in apoptosis response to cisplatin. PNAS, 100(5):2420-2425.

[69]Simon, L., Brunborg, G., Stevenson, M., et al., 2010. Clinical significance of sperm DNA damage in assisted reproduction outcome. Hum. Reprod., 25(7):1594-1608.

[70]Sollars, V., Lu, X., Xiao, L., et al., 2003. Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution. Nat. Genet., 33(1):70-74.

[71]Stojic, L., Cejka, P., Jiricny, J., 2005. High doses of SN1 type methylating agents activate DNA damage signaling cascades that are largely independent of mismatch repair. Cell Cycle, 4(3):473-477.

[72]Surtees, J.A., Argueso, J.L., Alani, E., 2004. Mismatch repair proteins:key regulators of genetic recombination. Cytogenet. Genome Res., 107(3-4):146-159.

[73]Terribas, E., Bonache, S., Garcia-Arevalo, M., et al., 2010. Changes in the expression profile of the meiosis-involved mismatch repair genes in impaired human spermatogenesis. J. Androl., 31(4):346-357.

[74]Thompson, J.R., Williams, C.J., 2005. Genomic imprinting and assisted reproductive technology: connections and potential risks. Semin. Reprod. Med., 23(3):285-295.

[75]Valentini, A.M., Armentano, R., Pirrelli, M., et al., 2006. Chemotherapeutic agents for colorectal cancer with a defective mismatch repair system: the state of the art. Cancer Treat. Rev., 32(8):607-618.

[76]van Montfoort, A.P., Hanssen, L.L., de Sutter, P., et al., 2012. Assisted reproduction treatment and epigenetic inheritance. Hum. Reprod. Update, 18(2):171-197.

[77]Wang, L.Y., Wang, N., Le, F., et al., 2013. Persistence and intergenerational transmission of differentially expressed genes in the testes of intracytoplasmic sperm injection conceived mice. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 14(5):372-381.

[78]Wang, Y., Qin, J., 2003. MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation. PNAS, 100(26):15387-15392.

[79]Watson, P., Lynch, H.T., 1994. The tumor spectrum in HNPCC. Anticancer Res., 14(4B):1635-1639.

[80]Wei, K., Clark, A.B., Wong, E., et al., 2003. Inactivation of Exonuclease 1 in mice results in DNA mismatch repair defects, increased cancer susceptibility, and male and female sterility. Genes Dev., 17(5):603-614.

[81]Win, A.K., Dowty, J.G., Antill, Y.C., et al., 2011. Body mass index in early adulthood and endometrial cancer risk for mismatch repair gene mutation carriers. Obstet. Gynecol., 117(4):899-905.

[82]Woldringh, G.H., Besselink, D.E., Tillema, A.H., et al., 2010. Karyotyping, congenital anomalies and follow-up of children after intracytoplasmic sperm injection with non-ejaculated sperm: a systematic review. Hum. Reprod. Update, 16(1):12-19.

[83]Wu, Y., Berends, M.J., Sijmons, R.H., et al., 2001. A role for MLH3 in hereditary nonpolyposis colorectal cancer. Nat. Genet., 29(2):137-138.

[84]Xu, K., Lu, T., Zhou, H., et al., 2010. The role of MSH5 C85T and MLH3 C2531T polymorphisms in the risk of male infertility with azoospermia or severe oligozoospermia. Clin. Chim. Acta, 411(1-2):49-52.

[85]Yi, W., Wu, X., Lee, T.H., et al., 2005. Two variants of MutS homolog hMSH5: prevalence in humans and effects on protein interaction. Biochem. Biophys. Res. Commun., 332(2):524-532.

[86]Youn, C.K., Cho, H.J., Kim, S.H., et al., 2005. Bcl-2 expression suppresses mismatch repair activity through inhibition of E2F transcriptional activity. Nat. Cell Biol., 7(2):137-147.

[87]Zheng, P., Schramm, R.D., Latham, K.E., 2005. Developmental regulation and in vitro culture effects on expression of DNA repair and cell cycle checkpoint control genes in rhesus monkey oocytes and embryos. Biol. Reprod., 72(6):1359-1369.

[88]Zheng, Y.M., Li, L., Zhou, L.M., et al., 2013. Alterations in the frequency of trinucleotide repeat dynamic mutations in offspring conceived through assisted reproductive technology. Hum. Reprod., 28(9):2570-2580.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2022 Journal of Zhejiang University-SCIENCE