A vertebrate gene, ticrr, is an essential checkpoint and replication regulator
A vertebrate gene, ticrr, is an essential checkpoint and replication regulator
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DOI：
10.1101/gad.1860310
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发表时间：
2010-01-15
影响因子：
10.5
通讯作者：
Lees, Jacqueline A.
中科院分区：
文献类型：
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作者：
Sansam, Christopher L.;Cruz, Nelly M.;Lees, Jacqueline A.
真核生物在正常细胞分裂和对DNA损伤的反应中有许多检查点途径来保护基因组的保真度。通过筛选斑马鱼的G2/M检查点调节因子，我们发现了ticrr （topbp1相互作用、检查点和复制调节因子），这是一个以前未被发现的基因，在电离辐射治疗后需要阻止有丝分裂进入。在没有外源性DNA损伤的情况下，Ticrr缺乏症是胚胎致死性的，因为它是正常细胞周期进程所必需的。具体来说，tirr的缺失会损害DNA复制并破坏S/M检查点，导致有丝分裂过早进入和有丝分裂灾难。我们发现，人类TICRR同源物与TopBP1相关，TopBP1是一种已知的检查点蛋白，也是DNA复制预起始复合物（pre-IC）的核心成分，并且在没有染色质的情况下，TICRR-TopBP1的相互作用是稳定的，并且需要BRCT基序来实现TopBP1的复制和检查点功能。最重要的是，我们发现tirr缺陷破坏了预复制复合物组分的染色质结合，而不是预复制复合物组分。综上所述，我们的数据表明，TICRR与TopBP1相关，并在ic前期形成中发挥重要作用。尚不清楚Ticrr是否代表酵母前ic成分Sld3的脊椎动物同源物，还是迄今未知的后生动物复制和检查点调节因子。
Eukaryotes have numerous checkpoint pathways to protect genome fidelity during normal cell division and in response to DNA damage. Through a screen for G2/M checkpoint regulators in zebrafish, we identified ticrr (for TopBP1-interacting, checkpoint, and replication regulator), a previously uncharacterized gene that is required to prevent mitotic entry after treatment with ionizing radiation. Ticrr deficiency is embryonic-lethal in the absence of exogenous DNA damage because it is essential for normal cell cycle progression. Specifically, the loss of ticrr impairs DNA replication and disrupts the S/M checkpoint, leading to premature mitotic entry and mitotic catastrophe. We show that the human TICRR ortholog associates with TopBP1, a known checkpoint protein and a core component of the DNA replication preinitiation complex (pre-IC), and that the TICRR-TopBP1 interaction is stable without chromatin and requires BRCT motifs essential for TopBP1's replication and checkpoint functions. Most importantly, we find that ticrr deficiency disrupts chromatin binding of pre-IC, but not prereplication complex, components. Taken together, our data show that TICRR acts in association with TopBP1 and plays an essential role in pre-IC formation. It remains to be determined whether Ticrr represents the vertebrate ortholog of the yeast pre-IC component Sld3, or a hitherto unknown metazoan replication and checkpoint regulator.