Ben Hassine Samia, Arcangioli Benoit
Dynamic of the Genome Unit, Genomes and Genetic Department, Institut Pasteur, URA2171, Paris, France.
EMBO J. 2009 Mar 18;28(6):632-40. doi: 10.1038/emboj.2009.9. Epub 2009 Feb 5.
In humans, a mutation in the tyrosyl-DNA phosphodiesterase (Tdp1) is responsible for the recessively inherited syndrome spinocerebellar ataxia with axonal neuropathy (SCAN1). Tdp1 is a well-conserved DNA repair enzyme, which processes modified 3' phospho-DNA adducts in vitro. Here, we report that in the yeast Schizosaccharomyces pombe, tdp1 mutant cells progressively accumulate DNA damage and rapidly lose viability in a physiological G0/quiescent state. Remarkably, this effect is independent of topoisomerase I function. Moreover, we provide evidence that Tdp1, with the polynucleotide kinase (Pnk1), processes the same naturally occurring 3'-ends, produced from oxidative DNA damage in G0. We also found that one half of the dead cells lose their nuclear DNA. Nuclear DNA degradation is genetically programmed and mainly depends on the two DNA damage checkpoint responses, ATM/Tel1 and ATR/Rad3, reminiscent to programmed cell death. Diminishing the respiration rate or treating cells with a low concentration of antioxidants rescues the quiescent tdp1 mutant cells. These findings suggest that mitochondrial respiration causes neuronal cell death in the SCAN1 syndrome and in other neurological disorders.
在人类中，酪氨酰 - DNA磷酸二酯酶（Tdp1）的突变是隐性遗传综合征伴轴索性神经病变的脊髓小脑共济失调（SCAN1）的病因。Tdp1是一种高度保守的DNA修复酶，它在体外可处理修饰的3'磷酸 - DNA加合物。在此，我们报告在裂殖酵母中，tdp1突变细胞在生理G0/静止状态下会逐渐积累DNA损伤并迅速丧失活力。值得注意的是，这种效应与拓扑异构酶I的功能无关。此外，我们提供证据表明，Tdp1与多核苷酸激酶（Pnk1）一起处理由G0期氧化DNA损伤产生的相同天然3'末端。我们还发现，一半的死亡细胞会丢失其核DNA。核DNA降解是由基因编程的，主要依赖于两种DNA损伤检查点反应，即ATM/Tel1和ATR/Rad3，这类似于程序性细胞死亡。降低呼吸速率或用低浓度抗氧化剂处理细胞可挽救静止的tdp1突变细胞。这些发现表明，线粒体呼吸导致了SCAN1综合征及其他神经疾病中的神经元细胞死亡。
