Delineation of a minimal topoisomerase II binding protein 1 for regulated activation of ATR at DNA double-strand breaks.
Delineation of a minimal topoisomerase II binding protein 1 for regulated activation of ATR at DNA double-strand breaks.
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描绘了在DNA双链断裂时调节ATR激活的最小拓扑异构酶II结合蛋白1。
DOI：
10.1016/j.jbc.2022.101992
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发表时间：
2022-07
影响因子：
4.8
通讯作者：
Michael, W. Matthew
中科院分区：
文献类型：
--
作者：
Ruis, Kenna;Huynh, Oanh;Montales, Katrina;Barr, Nina A.;Michael, W. Matthew
拓扑异构酶II结合蛋白1（TOPBP 1）是DNA损伤反应激酶共济失调毛细血管扩张和Rad 3相关（ATR）的重要激活剂，尽管这种激活发生的机制尚不清楚。TOPBP 1含有9个拷贝的BRCA 1 C-末端重复序列（BRCT）基序，它允许蛋白质-蛋白质和蛋白质-DNA相互作用。TOPBP 1还含有ATR激活结构域（AAD），其以刺激ATR激酶活性的方式与ATR及其伴侣ATR相互作用蛋白（ATRIP）物理相互作用。目前还不清楚TOPBP 1的9个BRCT结构域中的哪一个参与了反应，以及这些相关BRCT结构域所扮演的个体角色。为了解决这一知识缺口，在这里，我们描绘了一个最小的TOPBP 1，可以激活ATR在DNA双链断裂的调节方式。我们将这个最小的TOPBP 1命名为“Junior”，我们发现Junior仅由三个区域组成：BRCT 0 -2，AAD和BRCT 7和8。我们进一步定义了这三个区域的各自功能，表明BRCT 0 -2是招募DNA双链断裂所必需的，此后被激活，BRCT 7和8是招募所必需的，但对AAD多聚化和激活ATR至关重要。TOPBP 1 Junior的描述创建了一个更精简，简化和更好理解的TOPBP 1，并提供了对ATR激活机制的深入了解。
Topoisomerase II Binding Protein 1 (TOPBP1) is an important activator of the DNA damage response kinase Ataxia Telangiectasia and Rad3-related (ATR), although the mechanism by which this activation occurs is not yet known. TOPBP1 contains nine copies of the BRCA1 C-terminal repeat (BRCT) motif, which allows protein–protein and protein–DNA interactions. TOPBP1 also contains an ATR activation domain (AAD), which physically interacts with ATR and its partner ATR-interacting protein (ATRIP) in a manner that stimulates ATR kinase activity. It is unclear which of TOPBP1’s nine BRCT domains participate in the reaction, as well as the individual roles played by these relevant BRCT domains. To address this knowledge gap, here, we delineated a minimal TOPBP1 that can activate ATR at DNA double-strand breaks in a regulated manner. We named this minimal TOPBP1 “Junior” and we show that Junior is composed of just three regions: BRCT0-2, the AAD, and BRCT7&8. We further defined the individual functions of these three regions by showing that BRCT0-2 is required for recruitment to DNA double-strand breaks and is dispensable thereafter, and that BRCT7&8 is dispensable for recruitment but essential to allow the AAD to multimerize and activate ATR. The delineation of TOPBP1 Junior creates a leaner, simplified, and better understood TOPBP1 and provides insight into the mechanism of ATR activation.
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影响因子：
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作者：
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