Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Int J Mol Sci. 2019 Jun 20;20(12):3015. doi: 10.3390/ijms20123015.
Mammalian mitochondria contain four topoisomerases encoded in the nuclear genome: TOP1MT, TOP2α, TOP2β, and TOP3α. They also contain the two known tyrosyl-DNA phosphodiesterases (TDPs): TDP1 and TDP2, including a specific TDP2 isoform. Both TDP1 and TDP2 excise abortive topoisomerase cleavage complexes (TOPccs), yet their molecular structures and mechanisms are different. TDP1 is present across eukaryotes, from yeasts to humans and belongs to the phospholipase D family. It functions without a metal cofactor and has a broad activity range, as it also serves to cleanse blocking 3'-DNA ends bearing phosphoglycolate, deoxyribose phosphate, nucleoside, nucleoside analogs (zidovudine), abasic moieties, and with a lower efficiency, TOP2ccs. Found in higher vertebrates, TDP2 is absent in yeast where TDP1 appears to perform its functions. TDP2 belongs to the exonuclease/endonuclease/phosphodiesterase family and requires magnesium as a cofactor to excise TOP2ccs, and it also excises TOP1ccs, albeit with a lower efficiency. Here, we review TDP1 and TDP2 in the context of mitochondrial DNA repair and discuss potential new research areas centered on the mitochondrial TDPs.
TOP1MT、TOP2α、TOP2β 和 TOP3α。它们还含有两种已知的酪氨酸-DNA 磷酸二酯酶（TDP）：TDP1 和 TDP2，包括一种特定的 TDP2 同工型。TDP1 和 TDP2 都能切除有缺陷的拓扑异构酶切割复合物（TOPccs），但它们的分子结构和机制不同。TDP1 存在于从酵母到人类的所有真核生物中，属于磷脂酶 D 家族。它不需要金属辅因子就能发挥作用，具有广泛的活性范围，因为它还能清除带有磷酸甘油酸、脱氧核糖磷酸、核苷、核苷类似物（齐多夫定）、无碱基部分的阻塞 3'-DNA 末端，以及效率较低的 TOP2ccs。TDP2 存在于高等脊椎动物中，而在酵母中不存在，酵母中似乎由 TDP1 来执行其功能。TDP2 属于核酸外切酶/内切酶/磷酸二酯酶家族，需要镁作为辅因子才能切除 TOP2ccs，它也能切除 TOP1ccs，尽管效率较低。在这里，我们将在 mtDNA 修复的背景下讨论 TDP1 和 TDP2，并讨论以线粒体 TDP 为中心的潜在新研究领域。
