Cell cycle control in archaea

地球上的所有生命可以分为三个领域，真细菌、古细菌和真核生物(植物、动物、真菌等)。虽然真细菌和古细菌细胞往往很小，组织也很简单，但几乎所有的真核细胞都很大，有着极其复杂的内部结构。在细胞生长和分裂过程中维持这种秩序需要一套精心设计的分子机器。在20世纪70年代，Lee Hartwell和Paul Nurse在开创性的遗传学研究中发现了许多参与协调复杂真核细胞中细胞生长和分裂的核心“细胞分裂周期”机制。这一知识现在支撑了许多生物医学，从细胞分裂的控制出错的癌症到再生医学。直到最近，人们还不清楚复杂的真核细胞可能是如何出现的。然而，现在，随着对不同环境的调查，以识别不能使用元基因组测序培养的有机体的基因组，人们已经清楚地看到，许多维持真核细胞动态内部组织的机器都起源于古生菌。因此，要更好地了解真核生物的起源，就需要更好地了解古生物细胞生物学--更具体地说，研究与我们关系最密切的TACK/LOKI家族古菌。目前，对我们的古生物起源进行实验研究的最好的模式系统是Sulfolobus(Tack-Family古生菌的成员)。重要的是，Sulfolobus的细胞分裂周期似乎以与真核细胞周期相似的方式排序。然而，人们对参与其调控的分子机制知之甚少。这既是因为古生菌研究的匮乏，也是因为在一个小型极端微生物中进行细胞生物学研究的困难。我们的目标是改变这一点。由于Sulfolobus分子遗传学的最新发展，廉价的全基因组测序(使突变基因能够被克隆)和超分辨率显微镜(使这些小细胞能够用光成像)的发展，现在是使用Sulfolobus作为实验模型来确定古生菌细胞分裂周期的结构和识别参与其调控的分子机器的完美时机。例如，这将使我们能够确定古生菌是否有真核生物中的细胞周期时钟，以及真核生物中用于将DNA复制与细胞分裂相结合的检查点。通过这样做，我们有望了解更多关于地球生命这一未被研究的领域的信息。此外，我们希望这项工作能让我们更好地了解我们的起源，以及真核细胞分裂周期的功能，真核细胞分裂周期在人类发育、动态平衡和疾病中发挥着如此重要的作用。

All life on earth can be divided up into three domains, eubacteria, archaea and eukaryotes (plants, animals, fungi etc). While eubacteria and archaeal cells tend to be small and to be simple in organisation, almost all eukaryote cells are large and share an extraordinarily complex internal architecture. Maintaining this order as cells grow and divide requires an elaborate set of molecular machines. Much of the core "cell division cycle" machinery involved in coordinating cell growth and division in complex eukaryotic cells was identified in pioneering genetic studies in the 1970s by Lee Hartwell and Paul Nurse. This knowledge now underpins much of biomedicine, from cancer, where the control of cell division goes awry, to regenerative medicine.Until very recently it was not clear how complex eukaryotic cells might have arisen. Now, however, as the result of surveys of different environments to identify the genomes of organisms that can't be cultivated using metagenomic sequencing, it has become clear that many of the machines that function to maintain the dynamic internal organisation of eukaryote cells have their origins in archaea. An improved understanding of the origins of eukaryotes therefore requires a better understanding of archaeal cell biology - more specifically studies in TACK/Loki-family archaea to which we are most closely related. Currently, far and away the best model system in which to carry out experimental research into our archaeal origins is Sulfolobus (a member of the TACK-family archaea). Importantly, Sulfolobus has a cell division cycle that seems to be ordered in a similar way to the eukaryotic cell cycle. However, little is known about the molecular machinery involved in its regulation. This is both because of the paucity of research in archaea, and the difficulties of doing cell biology in a small extremophile. We aim to change this. As the result of the recent development of Sulfolobus molecular genetics, cheap whole genomic sequencing (enabling mutant genes to be cloned) and the development of super-resolution microscopy (which enables these small cells to be imaged using light) now is the perfect time to use Sulfolobus as an experimental model to determine how the archaea cell division cycle is structured and to identify the molecular machines involved in its regulation. This will enable us to determine for example whether archaea have a cell cycle clock like that found in eukaryotes and checkpoints like those used to couple DNA replication to cell division in eukaryotes.By doing so we expect to learn much about this understudied domain of life of earth. In addition, we expect this work to give us a better understanding of our origins, and of the function of the eukaryotic cell division cycle, which plays such an important role in human development, homeostasis and disease.