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Enzymatic DNA oxidation: mechanisms and biological significance

Guo-Liang Xu|Colum P. Walsh
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2014.11|BMB Reports|제47권 제11호|pp. 609-618

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참고문헌

키워드

TDGDNA demethylationEpigenetic reprogrammingTet dioxygenase5hmC
주제분류화학

초록

DNA methylation at cytosines (5mC) is a major epigeneticmodification involved in the regulation of multiple biologicalprocesses in mammals. How methylation is reversed was untilrecently poorly understood. The family of dioxygenasescommonly known as Ten-eleven translocation (Tet) proteinsare responsible for the oxidation of 5mC into three new forms,5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and5-carboxylcytosine (5caC). Current models link Tet-mediated5mC oxidation with active DNA demethylation. The higheroxidation products (5fC and 5caC) are recognized and excisedby the DNA glycosylase TDG via the base excision repairpathway. Like DNA methyltransferases, Tet enzymes areimportant for embryonic development. We will examine themechanism and biological significance of Tet-mediated 5mCoxidation in the context of pronuclear DNA demethylation inmouse early embryos. In contrast to its role in activedemethylation in the germ cells and early embryo, a numberof lines of evidence suggest that the intragenic 5hmC presentin brain may act as a stable mark instead. This short reviewexplores mechanistic aspects of TET oxidation activity, theimpact Tet enzymes have on epigenome organization andtheir contribution to the regulation of early embryonic andneuronal development.

Abstract

DNA methylation at cytosines (5mC) is a major epigeneticmodification involved in the regulation of multiple biologicalprocesses in mammals. How methylation is reversed was untilrecently poorly understood. The family of dioxygenasescommonly known as Ten-eleven translocation (Tet) proteinsare responsible for the oxidation of 5mC into three new forms,5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and5-carboxylcytosine (5caC). Current models link Tet-mediated5mC oxidation with active DNA demethylation. The higheroxidation products (5fC and 5caC) are recognized and excisedby the DNA glycosylase TDG via the base excision repairpathway. Like DNA methyltransferases, Tet enzymes areimportant for embryonic development. We will examine themechanism and biological significance of Tet-mediated 5mCoxidation in the context of pronuclear DNA demethylation inmouse early embryos. In contrast to its role in activedemethylation in the germ cells and early embryo, a numberof lines of evidence suggest that the intragenic 5hmC presentin brain may act as a stable mark instead. This short reviewexplores mechanistic aspects of TET oxidation activity, theimpact Tet enzymes have on epigenome organization andtheir contribution to the regulation of early embryonic andneuronal development.

참고문헌 (81)

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