{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:34:19Z","timestamp":1760240059494,"version":"build-2065373602"},"reference-count":73,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,3,4]],"date-time":"2019-03-04T00:00:00Z","timestamp":1551657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsches Krebsforschungszentrum (DKFZ) and Israel\u2019s Ministry of Science and Technology (MOST)","award":["CA 155"],"award-info":[{"award-number":["CA 155"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Supplementation of micronutrients like folate is a double-edged sword in terms of their ambivalent role in cell metabolism. Although several epidemiological studies support a protective role of folate in carcinogenesis, there are also data arguing for an opposite effect. To address this issue in the context of human papillomavirus (HPV)-induced transformation, the molecular events of different folate availability on human keratinocytes immortalized by HPV16 E6 and E7 oncoproteins were examined. Several sublines were established: Control (4.5 \u00b5M folate), folate deficient (0.002 \u00b5M folate), and repleted cells (4.5 \u00b5M folate). Cells were analyzed in terms of oncogene expression, DNA damage and repair, karyotype changes, whole-genome sequencing, and transcriptomics. Here we show that folate depletion irreversibly induces DNA damage, impairment of DNA repair fidelity, and unique chromosomal alterations. Repleted cells additionally underwent growth advantage and enhanced clonogenicity, while the above mentioned impaired molecular properties became even more pronounced. Overall, it appears that a period of folate deficiency followed by repletion can shape immortalized cells toward an anomalous phenotype, thereby potentially contributing to carcinogenesis. These observations should elicit questions and inquiries for broader additional studies regarding folate fortification programs, especially in developing countries with micronutrient deficiencies and high HPV prevalence.<\/jats:p>","DOI":"10.3390\/ijms20051100","type":"journal-article","created":{"date-parts":[[2019,3,4]],"date-time":"2019-03-04T05:22:26Z","timestamp":1551676946000},"page":"1100","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Folate Repletion after Deficiency Induces Irreversible Genomic and Transcriptional Changes in Human Papillomavirus Type 16 (HPV16)-Immortalized Human Keratinocytes"],"prefix":"10.3390","volume":"20","author":[{"given":"Claudia","family":"Savini","sequence":"first","affiliation":[{"name":"Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruwen","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larisa","family":"Savelyeva","sequence":"additional","affiliation":[{"name":"Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elke","family":"G\u00f6ckel-Krzikalla","sequence":"additional","affiliation":[{"name":"Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1523-2093","authenticated-orcid":false,"given":"Agnes","family":"Hotz-Wagenblatt","sequence":"additional","affiliation":[{"name":"Omics IT and Data Management, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Westermann","sequence":"additional","affiliation":[{"name":"Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"R\u00f6sl","sequence":"additional","affiliation":[{"name":"Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1093\/jn\/129.4.779","article-title":"Folate metabolism and requirements","volume":"129","author":"Bailey","year":"1999","journal-title":"J. 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