{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T17:27:28Z","timestamp":1788283648433,"version":"build-2803163510"},"reference-count":126,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,22]],"date-time":"2023-01-22T00:00:00Z","timestamp":1674345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Beijing Natural Science Foundation","award":["7222016"],"award-info":[{"award-number":["7222016"]}]},{"name":"the Beijing Natural Science Foundation","award":["CXYJ-2021-03"],"award-info":[{"award-number":["CXYJ-2021-03"]}]},{"name":"Research Foundation of Capital Institute of Pediatrics","award":["7222016"],"award-info":[{"award-number":["7222016"]}]},{"name":"Research Foundation of Capital Institute of Pediatrics","award":["CXYJ-2021-03"],"award-info":[{"award-number":["CXYJ-2021-03"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neural tube defects (NTDs) are complex congenital malformations resulting from failure of neural tube closure during embryogenesis, which is affected by the interaction of genetic and environmental factors. It is well known that folate deficiency increases the incidence of NTDs; however, the underlying mechanism remains unclear. Folate deficiency not only causes DNA hypomethylation, but also blocks the synthesis of 2\u2032-deoxythymidine-5\u2032\u2013monophosphate (dTMP) and increases uracil misincorporation, resulting in genomic instabilities such as base mismatch, DNA breakage, and even chromosome aberration. DNA repair pathways are essential for ensuring normal DNA synthesis, genomic stability and integrity during embryonic neural development. Genomic instability or lack of DNA repair has been implicated in risk of development of NTDs. Here, we reviewed the relationship between folate deficiency, DNA repair pathways and NTDs so as to reveal the role and significance of DNA repair system in the pathogenesis of NTDs and better understand the pathogenesis of NTDs.<\/jats:p>","DOI":"10.3390\/ijms24032220","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T03:21:54Z","timestamp":1674616914000},"page":"2220","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Neural Tube Defects and Folate Deficiency: Is DNA Repair Defective?"],"prefix":"10.3390","volume":"24","author":[{"given":"Xiuwei","family":"Wang","sequence":"first","affiliation":[{"name":"Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialu","family":"Yu","sequence":"additional","affiliation":[{"name":"Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.ntt.2004.12.007","article-title":"Human neural tube defects: Developmental biology, epidemiology, and genetics","volume":"27","author":"Detrait","year":"2005","journal-title":"Neurotoxicol. Teratol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1146\/annurev-neuro-062012-170354","article-title":"Neural tube defects","volume":"37","author":"Greene","year":"2014","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"(2017). Practice Bulletin No. 187: Neural Tube Defects. Obstet. Gynecol., 130, e279\u2013e290.","DOI":"10.1097\/AOG.0000000000002412"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1002\/bdr2.1380","article-title":"Overview on neural tube defects: From development to physical characteristics","volume":"111","author":"Avagliano","year":"2019","journal-title":"Birth Defects Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1002\/bdr2.1893","article-title":"Maternal ethnicity and the prevalence of British pregnancies affected by neural tube defects","volume":"113","author":"Peake","year":"2021","journal-title":"Birth Defects Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"248","DOI":"10.11604\/pamj.2021.40.248.25286","article-title":"Prevalence and patterns of birth defects among newborns in southwestern Ethiopia: A retrospective study","volume":"40","author":"Geneti","year":"2021","journal-title":"Pan Afr. Med. J."},{"key":"ref_7","first-page":"61","article-title":"Neural Tube Defects and Micronutrients Deficiency Prevalence in Georgia","volume":"298","author":"Tsiklauri","year":"2020","journal-title":"Georgian Med. News"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1002\/humu.23397","article-title":"Genetic contribution of retinoid-related genes to neural tube defects","volume":"39","author":"Li","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"789","DOI":"10.3945\/ajcn.110.002766","article-title":"Shmt1 and de novo thymidylate biosynthesis underlie folate-responsive neural tube defects in mice","volume":"93","author":"Beaudin","year":"2011","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.ydbio.2008.10.020","article-title":"Defective ciliogenesis, embryonic lethality and severe impairment of the Sonic Hedgehog pathway caused by inactivation of the mouse complex A intraflagellar transport gene Ift122\/Wdr10, partially overlapping with the DNA repair gene Med1\/Mbd4","volume":"325","author":"Cortellino","year":"2009","journal-title":"Dev. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1002\/ajmg.a.30713","article-title":"Polymorphisms in DNA repair genes as risk factors for spina bifida and orofacial clefts","volume":"135","author":"Olshan","year":"2005","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4352","DOI":"10.3390\/ijerph10094352","article-title":"Neural tube defects, folic acid and methylation","volume":"10","author":"Imbard","year":"2013","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.ijdevneu.2007.09.012","article-title":"Developmental neurotoxicity role of cyclophosphamide on post-neural tube closure of rodents in vitro and in vivo","volume":"25","author":"Xiao","year":"2007","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1002\/jat.2901","article-title":"Role of methotrexate exposure in apoptosis and proliferation during early neurulation","volume":"34","author":"Wang","year":"2014","journal-title":"J. Appl. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1093\/nar\/gkw1208","article-title":"Folate deficiency facilitates recruitment of upstream binding factor to hot spots of DNA double-strand breaks of rRNA genes and promotes its transcription","volume":"45","author":"Xie","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1002\/jat.2769","article-title":"Influence of the antifolate drug Methotrexate on the development of murine neural tube defects and genomic instability","volume":"33","author":"Zhao","year":"2013","journal-title":"J. Appl. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.neuro.2009.12.011","article-title":"Folic acid and soybean isoflavone combined supplementation protects the post-neural tube closure defects of rodents induced by cyclophosphamide in vivo and in vitro","volume":"31","author":"Zhao","year":"2010","journal-title":"Neurotoxicology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s11010-014-2222-0","article-title":"Raltitrexed\u2019s effect on the development of neural tube defects in mice is associated with DNA damage, apoptosis, and proliferation","volume":"398","author":"Dong","year":"2015","journal-title":"Mol. Cell. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.reprotox.2011.05.020","article-title":"Valproic acid-induced DNA damage increases embryonic p27(KIP1) and caspase-3 expression: A mechanism for valproic-acid induced neural tube defects","volume":"32","author":"Tung","year":"2011","journal-title":"Reprod. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1002\/path.2643","article-title":"Genetics and development of neural tube defects","volume":"220","author":"Copp","year":"2010","journal-title":"J. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/tera.1420470112","article-title":"Intermittent pattern of neural tube closure in two strains of mice","volume":"47","author":"Golden","year":"1993","journal-title":"Teratology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1002\/ajmg.1320470528","article-title":"Evidence for multi-site closure of the neural tube in humans","volume":"47","author":"Kalousek","year":"1993","journal-title":"Am. J. Med. Genet."},{"key":"ref_23","first-page":"506","article-title":"Multiple sites of anterior neural tube closure in humans: Evidence from anterior neural tube defects (anencephaly)","volume":"95","author":"Golden","year":"1995","journal-title":"Pediatrics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/wdev.71","article-title":"Neural tube defects\u2014Disorders of neurulation and related embryonic processes","volume":"2","author":"Copp","year":"2013","journal-title":"Wiley Interdiscip. Rev. Dev. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15007","DOI":"10.1038\/nrdp.2015.7","article-title":"Spina bifida","volume":"1","author":"Copp","year":"2015","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1542\/peds.2005-1739","article-title":"Are encephaloceles neural tube defects?","volume":"118","author":"Rowland","year":"2006","journal-title":"Pediatrics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"201","DOI":"10.3389\/fncel.2020.00201","article-title":"Spinal Cord Injury in Myelomeningocele: Prospects for Therapy","volume":"14","author":"Janik","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1002\/pd.2206","article-title":"Development of the vertebrate central nervous system: Formation of the neural tube","volume":"29","author":"Greene","year":"2009","journal-title":"Prenat. Diagn."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/bdra.20333","article-title":"Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects","volume":"79","author":"Harris","year":"2007","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"659612","DOI":"10.3389\/fgene.2021.659612","article-title":"Gene Environment Interactions in the Etiology of Neural Tube Defects","volume":"12","author":"Finnell","year":"2021","journal-title":"Front. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"US Preventive Services Task Force, Bibbins-Domingo, K., Grossman, D.C., Curry, S.J., Davidson, K.W., Epling, J.W., Garcia, F.A., Kemper, A.R., Krist, A.H., and Kurth, A.E. (2017). Folic Acid Supplementation for the Prevention of Neural Tube Defects: US Preventive Services Task Force Recommendation Statement. JAMA, 317, 183\u2013189.","DOI":"10.1001\/jama.2016.19438"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4760","DOI":"10.3390\/nu5114760","article-title":"Folate deficiency and folic acid supplementation: The prevention of neural-tube defects and congenital heart defects","volume":"5","author":"Czeizel","year":"2013","journal-title":"Nutrients"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1056\/NEJM199212243272602","article-title":"Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation","volume":"327","author":"Czeizel","year":"1992","journal-title":"N. Engl. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.biochi.2015.11.006","article-title":"Absorption and blood\/cellular transport of folate and cobalamin: Pharmacokinetic and physiological considerations","volume":"126","author":"Alpers","year":"2016","journal-title":"Biochimie"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.dnarep.2019.02.014","article-title":"Deoxyuracil in DNA and disease: Genomic signal or managed situation?","volume":"77","author":"Chon","year":"2019","journal-title":"DNA Repair"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"21","DOI":"10.3945\/an.111.000992","article-title":"Folate and DNA methylation: A review of molecular mechanisms and the evidence for folate\u2019s role","volume":"3","author":"Crider","year":"2012","journal-title":"Adv. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.3233\/JAD-190477","article-title":"Association of Folate Metabolites and Mitochondrial Function in Peripheral Blood Cells in Alzheimer\u2019s Disease: A Matched Case-Control Study","volume":"70","author":"Lv","year":"2019","journal-title":"J. Alzheimers Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1017\/S1368980008002735","article-title":"Maternal serum vitamin B12, folate and homocysteine and the risk of neural tube defects in the offspring in a high-risk area of China","volume":"12","author":"Zhang","year":"2009","journal-title":"Public Health Nutr."},{"key":"ref_39","first-page":"S15","article-title":"Epidemiology, prenatal management, and prevention of neural tube defects","volume":"35","author":"Salih","year":"2014","journal-title":"Saudi Med. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1056\/NEJM199911113412001","article-title":"Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention","volume":"341","author":"Berry","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.3945\/ajcn.2009.28858","article-title":"Relation between hypomethylation of long interspersed nucleotide elements and risk of neural tube defects","volume":"91","author":"Wang","year":"2010","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1080\/15592294.2021.1878725","article-title":"Hypermethylation of PI3K-AKT signalling pathway genes is associated with human neural tube defects","volume":"17","author":"Tian","year":"2022","journal-title":"Epigenetics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1038\/s41390-021-01908-6","article-title":"Folate deficiency disturbs PEG10 methylation modifications in human spina bifida","volume":"92","author":"Lu","year":"2022","journal-title":"Pediatr. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4688","DOI":"10.1096\/fj.201801536R","article-title":"The effect of folic acid deficiency on FGF pathway via Brachyury regulation in neural tube defects","volume":"33","author":"Chang","year":"2019","journal-title":"FASEB J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.nbd.2013.01.014","article-title":"Histone modification mapping in human brain reveals aberrant expression of histone H3 lysine 79 dimethylation in neural tube defects","volume":"54","author":"Zhang","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3290","DOI":"10.1073\/pnas.94.7.3290","article-title":"Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage","volume":"94","author":"Blount","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1515\/CCLM.2007.355","article-title":"Small ubiquitin-like modifier-1 (SUMO-1) modification of thymidylate synthase and dihydrofolate reductase","volume":"45","author":"Anderson","year":"2007","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0083-6729(08)00413-5","article-title":"Methylenetetrahydrofolate reductase, common polymorphisms, and relation to disease","volume":"79","author":"Thomas","year":"2008","journal-title":"Vitam. Horm."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.1038\/sj.bjc.6603197","article-title":"Sensitivity of markers of DNA stability and DNA repair activity to folate supplementation in healthy volunteers","volume":"94","author":"Basten","year":"2006","journal-title":"Br. J. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.mrfmmm.2011.11.003","article-title":"Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity","volume":"733","author":"Fenech","year":"2012","journal-title":"Mutat. Res."},{"key":"ref_51","first-page":"211","article-title":"Nucleotide levels and incorporation of 5-fluorouracil and uracil into DNA of cells treated with 5-fluorodeoxyuridine","volume":"21","author":"Ingraham","year":"1982","journal-title":"Mol. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1073\/pnas.77.4.1956","article-title":"Methotrexate-induced misincorporation of uracil into DNA","volume":"77","author":"Goulian","year":"1980","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1016\/j.bcp.2005.08.016","article-title":"Determination of apoptosis, uracil incorporation, DNA strand breaks, and sister chromatid exchanges under conditions of thymidylate deprivation in a model of BER deficiency","volume":"70","author":"Li","year":"2005","journal-title":"Biochem. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.reprotox.2017.12.007","article-title":"Inhibition of thymidylate synthase affects neural tube development in mice","volume":"76","author":"Wang","year":"2018","journal-title":"Reprod. Toxicol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Chen, X., Shen, Y., Gao, Y., Zhao, H., Sheng, X., Zou, J., Lip, V., Xie, H., Guo, J., and Shao, H. (2013). Detection of copy number variants reveals association of cilia genes with neural tube defects. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054492"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1056\/NEJMra0804615","article-title":"DNA damage, aging, and cancer","volume":"361","author":"Hoeijmakers","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/B978-0-444-52891-9.00013-0","article-title":"Microcephaly","volume":"111","author":"Passemard","year":"2013","journal-title":"Handb. Clin. Neurol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.ajhg.2008.01.009","article-title":"The involvement of DNA-damage and -repair defects in neurological dysfunction","volume":"82","author":"Kulkarni","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"112679","DOI":"10.1016\/j.yexcr.2021.112679","article-title":"Balancing DNA repair to prevent ageing and cancer","volume":"405","author":"Stead","year":"2021","journal-title":"Exp. Cell Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1387\/ijdb.092970da","article-title":"Gene expression profiling identifies eleven DNA repair genes down-regulated during mouse neural crest cell migration","volume":"55","author":"Albino","year":"2011","journal-title":"Int. J. Dev. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.mrfmmm.2005.03.007","article-title":"Human DNA repair genes, 2005","volume":"577","author":"Wood","year":"2005","journal-title":"Mutat. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1146\/annurev.biochem.73.011303.073723","article-title":"Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints","volume":"73","author":"Sancar","year":"2004","journal-title":"Annu. Rev. Biochem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1111\/j.1471-4159.2006.03980.x","article-title":"The p53 family in nervous system development and disease","volume":"97","author":"Jacobs","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2732","DOI":"10.1038\/sj.emboj.7601703","article-title":"BRCA2 is required for neurogenesis and suppression of medulloblastoma","volume":"26","author":"Frappart","year":"2007","journal-title":"EMBO J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1007\/s00109-003-0477-0","article-title":"BRCA1 and p53: Compensatory roles in DNA repair","volume":"81","author":"Hartman","year":"2003","journal-title":"J. Mol. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.gde.2005.03.002","article-title":"DNA repair disorders causing malformations","volume":"15","author":"Hales","year":"2005","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1093\/jn\/nxaa090","article-title":"p53 Disruption Increases Uracil Accumulation in DNA of Murine Embryonic Fibroblasts and Leads to Folic Acid-Nonresponsive Neural Tube Defects in Mice","volume":"150","author":"Lachenauer","year":"2020","journal-title":"J. Nutr."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/ng0296-191","article-title":"Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities","volume":"12","author":"Gowen","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1007\/s12031-011-9676-2","article-title":"Altered methylation of the DNA repair gene MGMT is associated with neural tube defects","volume":"47","author":"Tran","year":"2012","journal-title":"J. Mol. Neurosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"16990","DOI":"10.1074\/jbc.M116.739664","article-title":"Structural Features and Functional Dependency on beta-Clamp Define Distinct Subfamilies of Bacterial Mismatch Repair Endonuclease MutL","volume":"291","author":"Fukui","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1146\/annurev-genet-112414-054722","article-title":"Eukaryotic Mismatch Repair in Relation to DNA Replication","volume":"49","author":"Kunkel","year":"2015","journal-title":"Annu. Rev. Genet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.pharmthera.2018.04.004","article-title":"DNA mismatch repair in cancer","volume":"189","author":"Baretti","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.3748\/wjg.v13.i12.1767","article-title":"Microsatellite instability and MLH1 promoter hypermethylation in colorectal cancer","volume":"13","author":"Niv","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1053\/j.gastro.2009.12.064","article-title":"Microsatellite instability in colorectal cancer","volume":"138","author":"Boland","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1111\/j.1572-0241.1998.00592.x","article-title":"Microsatellite instability in non-neoplastic mucosa of patients with ulcerative colitis: Effect of folate supplementation","volume":"93","author":"Cravo","year":"1998","journal-title":"Am. J. Gastroenterol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/ejhg.2011.242","article-title":"Association of genomic instability, and the methylation status of imprinted genes and mismatch-repair genes, with neural tube defects","volume":"20","author":"Liu","year":"2012","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.cell.2013.03.025","article-title":"The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSalpha","volume":"153","author":"Li","year":"2013","journal-title":"Cell"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2956","DOI":"10.1073\/pnas.0915033107","article-title":"Histone H3 lysine 36 methyltransferase Hypb\/Setd2 is required for embryonic vascular remodeling","volume":"107","author":"Hu","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"5","DOI":"10.2217\/epi-2019-0279","article-title":"Low folate concentration impacts mismatch repair deficiency in neural tube defects","volume":"12","author":"Li","year":"2020","journal-title":"Epigenomics"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/15443","article-title":"The DNA repair gene MBD4 (MED1) is mutated in human carcinomas with microsatellite instability","volume":"23","author":"Riccio","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0165-4608(03)00062-1","article-title":"MBD4 mutations are rare in gastric carcinomas with microsatellite instability","volume":"145","author":"Pinto","year":"2003","journal-title":"Cancer Genet. Cytogenet."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1002\/jcp.1064","article-title":"Role of MED1 (MBD4) Gene in DNA repair and human cancer","volume":"187","author":"Bellacosa","year":"2001","journal-title":"J. Cell. Physiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"a012583","DOI":"10.1101\/cshperspect.a012583","article-title":"Base excision repair","volume":"5","author":"Krokan","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2174\/1874467211205010003","article-title":"Overview of base excision repair biochemistry","volume":"5","author":"Kim","year":"2012","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1042\/EBC20200013","article-title":"Base excision repair and its implications to cancer therapy","volume":"64","author":"Grundy","year":"2020","journal-title":"Essays Biochem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.semcancer.2010.10.010","article-title":"Variant base excision repair proteins: Contributors to genomic instability","volume":"20","author":"Nemec","year":"2010","journal-title":"Semin. Cancer Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.molcel.2004.06.003","article-title":"AP endonuclease-independent DNA base excision repair in human cells","volume":"15","author":"Wiederhold","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1089\/ars.2010.3466","article-title":"Base excision repair and lesion-dependent subpathways for repair of oxidative DNA damage","volume":"14","author":"Svilar","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1016\/j.dnarep.2008.03.017","article-title":"Poly(ADP-ribose) polymerase-1 modulates DNA repair capacity and prevents formation of DNA double strand breaks","volume":"7","author":"Woodhouse","year":"2008","journal-title":"DNA Repair"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1126\/science.7624801","article-title":"Excision of deoxyribose phosphate residues by DNA polymerase beta during DNA repair","volume":"269","author":"Matsumoto","year":"1995","journal-title":"Science"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"4623","DOI":"10.1128\/MCB.05715-11","article-title":"Nucleosome disruption by DNA ligase III-XRCC1 promotes efficient base excision repair","volume":"31","author":"Odell","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"23970","DOI":"10.1074\/jbc.272.38.23970","article-title":"Involvement of XRCC1 and DNA ligase III gene products in DNA base excision repair","volume":"272","author":"Cappelli","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"9573","DOI":"10.1074\/jbc.271.16.9573","article-title":"Two pathways for base excision repair in mammalian cells","volume":"271","author":"Frosina","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1093\/emboj\/20.6.1477","article-title":"Human DNA polymerase beta initiates DNA synthesis during long-patch repair of reduced AP sites in DNA","volume":"20","author":"Podlutsky","year":"2001","journal-title":"EMBO J."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"3963","DOI":"10.1007\/s00018-018-2900-2","article-title":"Impact of DNA repair and stability defects on cortical development","volume":"75","author":"Bianchi","year":"2018","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"36504","DOI":"10.1074\/jbc.M405185200","article-title":"Imbalanced base excision repair in response to folate deficiency is accelerated by polymerase beta haploinsufficiency","volume":"279","author":"Cabelof","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.freeradbiomed.2010.11.003","article-title":"Folate deficiency regulates expression of DNA polymerase beta in response to oxidative stress","volume":"50","author":"Unnikrishnan","year":"2011","journal-title":"Free Radic. Biol. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1096\/fasebj.12.14.1491","article-title":"DNA instability (strand breakage, uracil misincorporation, and defective repair) is increased by folic acid depletion in human lymphocytes in vitro","volume":"12","author":"Duthie","year":"1998","journal-title":"FASEB J."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2592","DOI":"10.1007\/s43032-021-00537-y","article-title":"Genetic Polymorphisms in DNA Repair Gene APE1\/Ref-1 and the Risk of Neural Tube Defects in a High-Risk Area of China","volume":"28","author":"Wang","year":"2021","journal-title":"Reprod. Sci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"5015","DOI":"10.12659\/MSM.907492","article-title":"Polymorphism rs1052536 in Base Excision Repair Gene Is a Risk Factor in a High-Risk Area of Neural Tube Defects in China","volume":"24","author":"Li","year":"2018","journal-title":"Med. Sci. Monit."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1093\/nar\/gkv1312","article-title":"Nucleolar responses to DNA double-strand breaks","volume":"44","author":"Larsen","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.clon.2014.02.004","article-title":"DNA double-strand break repair in a cellular context","volume":"26","author":"Shibata","year":"2014","journal-title":"Clin. Oncol. (R. Coll. Radiol.)"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Spies, J., Polasek-Sedlackova, H., Lukas, J., and Somyajit, K. (2021). Homologous Recombination as a Fundamental Genome Surveillance Mechanism during DNA Replication. Genes, 12.","DOI":"10.3390\/genes12121960"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1093\/abbs\/gmz076","article-title":"Pathways and assays for DNA double-strand break repair by homologous recombination","volume":"51","author":"Li","year":"2019","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Huselid, E., and Bunting, S.F. (2020). The Regulation of Homologous Recombination by Helicases. Genes, 11.","DOI":"10.3390\/genes11050498"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"3413","DOI":"10.1038\/emboj.2009.276","article-title":"ATM and Artemis promote homologous recombination of radiation-induced DNA double-strand breaks in G2","volume":"28","author":"Beucher","year":"2009","journal-title":"EMBO J."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.tibs.2017.06.011","article-title":"A Process of Resection-Dependent Nonhomologous End Joining Involving the Goddess Artemis","volume":"42","author":"Lobrich","year":"2017","journal-title":"Trends Biochem. Sci."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.neuron.2014.06.034","article-title":"DNA damage and its links to neurodegeneration","volume":"83","author":"Madabhushi","year":"2014","journal-title":"Neuron"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/nrm.2017.48","article-title":"Non-homologous DNA end joining and alternative pathways to double-strand break repair","volume":"18","author":"Chang","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1146\/annurev.biochem.052308.093131","article-title":"The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway","volume":"79","author":"Lieber","year":"2010","journal-title":"Annu. Rev. Biochem."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.dnarep.2018.08.019","article-title":"DNA double-strand breaks as drivers of neural genomic change, function, and disease","volume":"71","author":"Alt","year":"2018","journal-title":"DNA Repair"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1111\/jcmm.17119","article-title":"Studying the mechanism of sperm DNA damage caused by folate deficiency","volume":"26","author":"Wang","year":"2022","journal-title":"J. Cell. Mol. Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s13072-019-0312-7","article-title":"Folate deficiency induced H2A ubiquitination to lead to downregulated expression of genes involved in neural tube defects","volume":"12","author":"Pei","year":"2019","journal-title":"Epigenet. Chromatin"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"9831","DOI":"10.1073\/pnas.0904172106","article-title":"Neural tube defects in mice with reduced levels of inositol 1,3,4-trisphosphate 5\/6-kinase","volume":"106","author":"Wilson","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1093\/emboj\/21.8.2038","article-title":"Specific interaction of IP6 with human Ku70\/80, the DNA-binding subunit of DNA-PK","volume":"21","author":"Hanakahi","year":"2002","journal-title":"EMBO J."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/S0092-8674(00)00061-1","article-title":"Binding of inositol phosphate to DNA-PK and stimulation of double-strand break repair","volume":"102","author":"Hanakahi","year":"2000","journal-title":"Cell"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1093\/emboj\/18.5.1172","article-title":"Telomere shortening in mTR\u2212\/\u2212 embryos is associated with failure to close the neural tube","volume":"18","author":"Herrera","year":"1999","journal-title":"EMBO J."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ydbio.2004.06.023","article-title":"Telomere biology in mammalian germ cells and during development","volume":"274","author":"Bekaert","year":"2004","journal-title":"Dev. Biol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1006\/dbio.1999.9232","article-title":"Requirement for the Xrcc1 DNA base excision repair gene during early mouse development","volume":"208","author":"Tebbs","year":"1999","journal-title":"Dev. Biol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"8919","DOI":"10.1073\/pnas.93.17.8919","article-title":"The redox\/DNA repair protein, Ref-1, is essential for early embryonic development in mice","volume":"93","author":"Xanthoudakis","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2697","DOI":"10.1111\/j.1582-4934.2010.01191.x","article-title":"The relationship between early embryo development and tumourigenesis","volume":"14","author":"Ma","year":"2010","journal-title":"J. Cell Mol. Med."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1007\/s13668-018-0237-y","article-title":"Folate and Its Impact on Cancer Risk","volume":"7","author":"Pieroth","year":"2018","journal-title":"Curr. Nutr. Rep."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.cancergencyto.2009.11.014","article-title":"MTHFR C677T and A1298C variant genotypes and the risk of microsatellite instability among Iranian colorectal cancer patients","volume":"197","author":"Naghibalhossaini","year":"2010","journal-title":"Cancer Genet. Cytogenet."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.eururo.2019.06.030","article-title":"Prostate-specific Membrane Antigen Heterogeneity and DNA Repair Defects in Prostate Cancer","volume":"76","author":"Paschalis","year":"2019","journal-title":"Eur. Urol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"e2019822118","DOI":"10.1073\/pnas.2019822118","article-title":"p53 deficiency induces MTHFD2 transcription to promote cell proliferation and restrain DNA damage","volume":"118","author":"Li","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_126","first-page":"264","article-title":"Inactivation of folylpolyglutamate synthetase Met7 results in genome instability driven by an increased dUTP\/dTTP ratio","volume":"48","author":"Schmidt","year":"2020","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2220\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:13:37Z","timestamp":1760120017000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2220"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,22]]},"references-count":126,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24032220"],"URL":"https:\/\/doi.org\/10.3390\/ijms24032220","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,22]]}}}