Background: For many human cell types including those of the intestinal epithelium and the immune system, rapid proliferation is essential for normal function. Proliferating cells exhibit increased growth and DNA synthesis which generate nutrient demands. In particular, we have shown that rapidly proliferating lymphocytes increase the uptake of the vitamin biotin five fold, suggesting that cell proliferation generates a substantial increase in biotin demand. This demand might arise from increased synthesis of biotin-dependent carboxylases or from biotinylation of histones (or both). Consistent with this hypothesis are our preliminary studies indicating that biotin deficiency causes reduced proliferation and cell cycle arrest. We hypothesize that biotin has an essential role in cell proliferation in some ways analogous to the role of folate in methylation of DNA regulating the cell cycle. Long-term objectives: To elucidate the role(s) of biotin in the regulation of cell cycle progression and to characterize effects of the cell cycle on cellular biotin homeostasis. Specific hypotheses: (1) At certain phases of the cell cycle, lymphocytes increase expression of the biotin transporter gene leading to increased synthesis of transporter and increase of biotin uptake. (2) In addition to holocarboxylase synthesis, biotin is required in a biotinidase-catalyzed, cell-cycle dependent biotinylation of histones.
Specific aims : (1) To quantitate biotin transporter mRNA and transport activity in lymphocytes at various phases of the cell cycle. (2) To quantitate biotinidase mRNA, cellular biotinidase activity, and biotinylation of histones at various phases of the cell cycle in lymphocytes from healthy adults and, for purposes of comparison, from biotinidase-deficient patients. (3) To investigate the intracellular trafficking of biotin and carboxylase activities. (4) To characterize the effect of extracellular biotin concentration in the culture medium on the proliferation rate of lymphocytes. Benefits: The proposed research will likely lead to novel insights into the mechanisms that generate the increased biotin requirement of proliferating cells. These studies are the initial step to determine whether biotin plays an important role in histone modification and cell cycle regulation. The basic knowledge generated may well be relevant to teratogenesis and immune dysfunction caused by biotin deficiency.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Nutrition Study Section (NTN)
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May, Michael K
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University of Nebraska Lincoln
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Camara Teixeira, Daniel; Cordonier, Elizabeth L; Wijeratne, Subhashinee S K et al. (2018) A cell death assay for assessing the mitochondrial targeting of proteins. J Nutr Biochem 56:48-54
Liu, Dandan; Zempleni, Janos (2014) Holocarboxylase synthetase interacts physically with nuclear receptor co-repressor, histone deacetylase 1 and a novel splicing variant of histone deacetylase 1 to repress repeats. Biochem J 461:477-86
Eng, Wei Kay; Giraud, David; Schlegel, Vicki L et al. (2013) Identification and assessment of markers of biotin status in healthy adults. Br J Nutr 110:321-9
Zempleni, Janos; Wijeratne, Subhashinee S K; Hassan, Yousef I (2009) Biotin. Biofactors 35:36-46
Camporeale, Gabriela; Chew, Yap Ching; Kueh, Alice et al. (2008) Use of synthetic peptides for identifying biotinylation sites in human histones. Methods Mol Biol 418:139-48
Herring, Theresa A; Cuppett, Susan L; Zempleni, Janos (2007) Genomic implications of H(2)O (2) for cell proliferation and growth of Caco-2 cells. Dig Dis Sci 52:3005-15
Chew, Yap Ching; Sarath, Gautam; Zempleni, Janos (2007) An avidin-based assay for histone debiotinylase activity in human cell nuclei. J Nutr Biochem 18:475-81
Griffin, Jacob B; Rodriguez-Melendez, Rocio; Dode, Leonard et al. (2006) Biotin supplementation decreases the expression of the SERCA3 gene (ATP2A3) in Jurkat cells, thus, triggering unfolded protein response. J Nutr Biochem 17:272-81
Chew, Yap Ching; Camporeale, Gabriela; Kothapalli, Nagarama et al. (2006) Lysine residues in N-terminal and C-terminal regions of human histone H2A are targets for biotinylation by biotinidase. J Nutr Biochem 17:225-33
Manthey, Karoline C; Rodriguez-Melendez, Rocio; Hoi, Jia Tse et al. (2006) Riboflavin deficiency causes protein and DNA damage in HepG2 cells, triggering arrest in G1 phase of the cell cycle. J Nutr Biochem 17:250-6

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