An Increase in Mitochondrial DNA Promotes Nuclear DNA Replication in Yeast

Coordination between cellular metabolism and DNA replication determines when cells initiate division. It has been assumed that metabolism only plays a permissive role in cell division. While blocking metabolism arrests cell division, it is not known whether an up-regulation of metabolic reactions accelerates cell cycle transitions. Here, we show that increasing the amount of mitochondrial DNA accelerates overall cell proliferation and promotes nuclear DNA replication, in a nutrient-dependent manner. The Sir2p NAD+-dependent de-acetylase antagonizes this mitochondrial role. We found that cells with increased mitochondrial DNA have reduced Sir2p levels bound at origins of DNA replication in the nucleus, accompanied with increased levels of K9, K14-acetylated histone H3 at those origins. Our results demonstrate an active role of mitochondrial processes in the control of cell division. They also suggest that cellular metabolism may impact on chromatin modifications to regulate the activity of origins of DNA replication.

细胞代谢与DNA复制之间的协同调控决定了细胞启动分裂的具体时机。此前学界普遍认为，代谢过程仅在细胞分裂中发挥许可性作用。尽管阻断代谢会阻滞细胞分裂，但目前仍不清楚代谢反应上调是否能够加速细胞周期进程。本研究显示，提升线粒体DNA（mitochondrial DNA）的含量能够以营养依赖的方式加速整体细胞增殖，并促进核DNA复制。依赖烟酰胺腺嘌呤二核苷酸（NAD+）的脱乙酰酶Sir2p会拮抗这一线粒体介导的效应。我们发现，线粒体DNA含量升高的细胞中，结合于细胞核内DNA复制起点的Sir2p水平显著降低，同时这些复制起点区域的K9、K14乙酰化组蛋白H3水平同步升高。本研究结果证实了线粒体过程在细胞分裂调控中的主动调控功能。同时，该研究也提示，细胞代谢或可通过影响染色质修饰来调控DNA复制起点的活性。