Mechanistic insights into the periodic control of transcription in the mammalian cell cycle

我们所有人都是由卵子受精产生的单个细胞发育成包含数百万个细胞的复杂人类。为了从这种单细胞状态过渡，细胞必须不断分裂成两个细胞，并在此过程中将其遗传蓝图（即DNA）的副本传递给新细胞。这个过程通常被称为细胞分裂。因此，了解控制这一过程的基本机制至关重要。相反，随着我们年龄的增长，细胞变得无法分裂，变得“衰老”。这就产生了一个问题，因为我们不能再产生新的细胞来取代旧的或受损的细胞。相反，细胞分裂的过度激活会导致癌症。事实上，癌症是一种由体内“正常细胞”功能失调引起的疾病，其中一种功能失调与细胞分裂有关。如果这个过程不受控制，大量的细胞就会发育，积累更多的损伤，最终导致肿瘤。因此，了解正常细胞分裂的关键过程以及最终在癌症中如何出错是至关重要的。这个项目旨在了解一个关键的调节因子FOXM1是如何控制细胞分裂的。这种调节因子的丰度在癌细胞中增加，但在衰老细胞中减少，使其成为控制这两个重要过程的纽带。FOXM1不是单独工作的，它有伙伴帮助它解码基因组的特定子部分，这一过程被称为转录。在这里，我们将研究已知的FOXM1的合作伙伴，并确定新的合作伙伴。我们将研究它们如何共同作用来控制细胞分裂。这将为确定我们发现的机制是否与衰老或癌症相关提供一个平台，并可能导致治疗策略的发展。

All of us develop into complex human beings containing millions of cells from a single cell created by fertilization of an egg. To transit from this single cell state, cells must continually divide into two cells, and in doing so pass a copy of their genetic blueprint (ie their DNA) to the new cells. This process is generally referred to as cell division. It is therefore critically important to understand the fundamental mechanisms that control this process. Conversely, as we age, cells become incapable of division and become "senescent". This creates a problem as we can no longer generate new cells to replace old or damaged cells. Conversely, hyperactivation of cell division leads to cancer. Indeed, cancer is a disease caused by the malfunction of "normal cells" in your body, and one of these malfunctions involves the onset of cell division. If this process goes unchecked, large masses of cells develop which accumulate more damage, and ultimately give rise to tumours. Thus understanding this critical process of cell division in normal cells and ultimately how this goes wrong in cancers is vitally important. This project aims to understand how one key regulator, FOXM1, works to control cell division. The abundance of this regulator is increased in cancer cells but is decreased in ageing cells, placing it at the nexus of control of these two important processes. FOXM1 does not work alone but has partners which help it to decode specific subparts of the genome in a process known as transcription. Here, we will study known partners and identify new partners for FOXM1. We will investigate how they work together to control cell division. This will provide a platform for establishing whether the mechanisms we uncover are relevant in the context of ageing or cancer and might lead to the development of therapeutic strategies.