Abstract

DNA replication is a highly precise process which usually functions in a perfect rhythm with cell cycle progression. However, cells are constantly faced with various kinds of obstacles such as blocks in DNA replication, lack of availability of precursors and improper chromosome alignment. When these problems are not addressed, they may lead to chromosome instability and the accumulation of mutations, and even cell death. Therefore, the cell has developed response mechanisms to keep most of these situations under control. Of the many factors that participate in this DNA damage response, members of the family of phosphatidylinositol 3-kinase-related protein kinases (PIKKs) orchestrate the response landscape. Our understanding of two members of the PIKK family, human ATR (yeast Mec1) and ATM (yeast Tel1), and their associated partner proteins, has shown substantial progress through recent biochemical and structural studies. Emerging structural information of these unique kinases show common features that reveal the mechanism of kinase activity.

摘要

DNA 复制是一个高度精确的过程，通常以完美的节奏与细胞周期进程一起发挥作用。然而，细胞不断面临各种障碍，例如 DNA 复制受阻、前体缺乏和染色体排列不当。如果不解决这些问题，它们可能会导致染色体不稳定和突变积累，甚至导致细胞死亡。因此，细胞已经开发出反应机制来控制大多数这些情况。在参与这种 DNA 损伤反应的许多因素中，磷脂酰肌醇 3-激酶相关蛋白激酶 (PIKK) 家族的成员协调了反应格局。我们对 PIKK 家族的两个成员，人类 ATR（酵母 Mec1）和 ATM（酵母 Tel1）及其相关伙伴蛋白的了解，通过最近的生化和结构研究显示出实质性进展。这些独特激酶的新兴结构信息显示出揭示激酶活性机制的共同特征。