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Abstract
The purpose of this review is to discuss the implications of the 2009 discovery of the sixth deoxyribonucleoside (dN) [5-hydroxymethyldeoxycytidine (hmdC)] in DNA which is the most abundant in neurons. The concurrent discovery of the three ten-eleven translocation enzymes (TET) which not only synthesize but also oxidize hmdC in DNA, prior to glycosylase removal and base excision repair, helps explain many heretofore unexplained phenomena in brain including: 1) the high concentration of ascorbic acid (AA) in neurons since AA is a cofactor for the TET enzymes, 2) the requirement for reduced folates and the dN synthetic enzymes in brain, 3) continued DNA synthesis in non-dividing neurons to repair the dynamic formation/removal of hmdC, and 4) the heretofore unexplained mechanism to remove 5-methyldeoxycytidine, the fifth nucleoside, from DNA. In these processes, we also describe the important role of choroid plexus and CSF in supporting vitamin homeostasis in brain: especially for AA and folates, for hmdC synthesis and removal, and methylated deoxycytidine (mdC) removal from DNA in brain. The nexus linking AA and folates to methylation, hydroxymethylation, and demethylation of DNA is pivotal to understanding not only brain development but also the subsequent function.
Highlights
For over forty years, we and myriad others have investigated fluid (CSF) production by choroid plexus (CP) [1,2,3], ion and pH homeostasis in CSF [4,5,6], vitamin transport and homeostasis in CSF and brain [7,8,9,10,11], and DNA precursor transport/synthesis as well as DNA synthesis in developing and adult brain [12,13]
Why do neurons require so much Ascorbic acid (AA) [20,24]? This puzzle has persisted for decades but, as described below, we have a convincing tentative answer
We review the relevant findings and implications, beginning in 2009, of the discovery of the sixth deoxyribonucleoside in DNA, hydroxymethyldeoxycytidine [28,29]
Summary
For over forty years, we and myriad others have investigated fluid (CSF) production by choroid plexus (CP) [1,2,3], ion and pH homeostasis in CSF [4,5,6], vitamin transport and homeostasis in CSF and brain [7,8,9,10,11], and DNA precursor transport/synthesis as well as DNA synthesis in developing and adult brain [12,13]. Implications and vistas As described we have sound explanations for: 1) the need for active powerful systems in CP to concentrate AA and folates in CSF for ‘nourishment’ of neurons, 2) the high concentrations of AA and folates in neurons, and 3) the exquisite control of the CSF transport, salvage, and formation of the precursors of DNA synthesis in adult and aged mammalian brain, a tissue with relatively few dividing cells. The authors carefully considered the BMC guidelines, and have read and approved the final manuscript
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