A kinase-independent function for AURORA-A in replisome assembly during DNA replication initiation
A kinase-independent function for AURORA-A in replisome assembly during DNA replication initiation
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DOI：
10.1093/nar/gkaa570
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发表时间：
2020-08-20
影响因子：
14.9
通讯作者：
Venkitaraman, Ashok R.
中科院分区：
文献类型：
--
作者：
Almeida, Estrella Guarino;Renaudin, Xavier;Venkitaraman, Ashok R.
人Aurora-A激酶(AURKA)的催化活性调节有丝分裂进程，其在主要类型的上皮性癌中的频繁过表达与非整倍体和肿瘤的发生有关。在这里，我们报告了AURKA在DNA复制启动中的一个意想不到的、不依赖于激酶的功能，它通过一类变构抑制剂的抑制打开了癌症治疗的途径。我们发现AURKA的基因缺失，或者它被变构而不是催化抑制剂抑制，阻止了G1-S细胞周期的转变。一个催化失活的AURKA突变体足以克服这一障碍。我们在AURKA和G1期间形成的复制体成分MCM7、WDHD1和POLD1之间发现了一个多蛋白复合体，并证明变构但不是催化抑制剂阻止了功能复制体的染色质组装。事实上，变构而不是催化的AURKA抑制剂使癌细胞对复制启动因子DDK的CDC7激酶亚单位的抑制敏感。因此，我们的发现定义了一种在DNA复制启动过程中复制体组装必不可少的机制，作为癌症的联合治疗，该机制容易受到抑制。
The catalytic activity of human AURORA-A kinase (AURKA) regulates mitotic progression, and its frequent overexpression in major forms of epithelial cancer is associated with aneuploidy and carcinogenesis. Here, we report an unexpected, kinase-independent function for AURKA in DNA replication initiation whose inhibition through a class of allosteric inhibitors opens avenues for cancer therapy. We show that genetic depletion of AURKA, or its inhibition by allosteric but not catalytic inhibitors, blocks the G1-S cell cycle transition. A catalytically inactive AURKA mutant suffices to overcome this block. We identify a multiprotein complex between AURKA and the replisome components MCM7, WDHD1 and POLD1 formed during G1, and demonstrate that allosteric but not catalytic inhibitors prevent the chromatin assembly of functional replisomes. Indeed, allosteric but not catalytic AURKA inhibitors sensitize cancer cells to inhibition of the CDC7 kinase subunit of the replication-initiating factor DDK. Thus, our findings define a mechanism essential for replisome assembly during DNA replication initiation that is vulnerable to inhibition as combination therapy in cancer.