ATR kinase inhibition induces unscheduled origin firing through a Cdc7-dependent association between GINS and And-1.
ATR kinase inhibition induces unscheduled origin firing through a Cdc7-dependent association between GINS and And-1.
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DOI：
10.1038/s41467-017-01401-x
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发表时间：
2017-11-09
影响因子：
16.6
通讯作者：
Bakkenist CJ
中科院分区：
文献类型：
--
作者：
Moiseeva T;Hood B;Schamus S;O'Connor MJ;Conrads TP;Bakkenist CJ
ATR激酶活性减缓复制叉并阻止受损细胞中的起始点激发。在这里，我们描述了蛋白质组学分析，确定ATR激酶抑制剂诱导未受损细胞的非计划起源放电的机制。ATR-Chk 1激酶诱导的起源放电由Cdc 7激酶介导，通过先前未描述的GINS磷酸化诱导GINS和And-1之间的关联。ATR-Chk 1受体诱导的起源放电被先前暴露于DNA损伤剂所阻断，表明起源放电的预防不需要持续的ATR活性。与此相反，ATR-Chk 1引物诱导的起点产生额外的复制叉，随后暴露于DNA损伤剂的目标。因此，ATR激酶抑制剂和DNA损伤剂的施用顺序影响由组合诱导的DNA损伤。我们的实验确定竞争ATR和Cdc 7激酶依赖的机制在人类细胞的复制起点。ATR激酶活性对于减缓复制叉和防止DNA损伤细胞中的DNA复制至关重要。在这里，作者表明ATR抑制导致GINS的Cdc 7磷酸化，导致起源放电。
ATR kinase activity slows replication forks and prevents origin firing in damaged cells. Here we describe proteomic analyses that identified mechanisms through which ATR kinase inhibitors induce unscheduled origin firing in undamaged cells. ATR-Chk1 inhibitor-induced origin firing is mediated by Cdc7 kinase through previously undescribed phosphorylations on GINS that induce an association between GINS and And-1. ATR-Chk1 inhibitor-induced origin firing is blocked by prior exposure to DNA damaging agents showing that the prevention of origin firing does not require ongoing ATR activity. In contrast, ATR-Chk1 inhibitor-induced origins generate additional replication forks that are targeted by subsequent exposure to DNA damaging agents. Thus, the sequence of administration of an ATR kinase inhibitor and a DNA damaging agent impacts the DNA damage induced by the combination. Our experiments identify competing ATR and Cdc7 kinase-dependent mechanisms at replication origins in human cells. ATR kinase activity is essential for slowing replication forks and preventing DNA replication in cells with DNA damage. Here the authors show that ATR inhibition leads to Cdc7 phosphorylation of GINS, leading to origin firing.
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DOI：
10.1073/pnas.94.11.5611
发表时间：
1997-05-27
影响因子：
11.1
作者：
Donovan, S;Harwood, J;Diffley, JFX
通讯作者：
Diffley, JFX
DOI：
10.1073/pnas.0804424105
发表时间：
2008-06-24
影响因子：
11.1
作者：
Aygun, Ozan;Svejstrup, Jesper;Liu, Yilun
通讯作者：
Liu, Yilun
影响因子：
10.5
作者：
Ge, Xin Quan;Jackson, Dean A;Blow, J Julian
通讯作者：
Blow, J Julian
影响因子：
3.5
作者：
Despras, Emmanuelle;Daboussi, Fayza;Kannouche, Patricia L.
通讯作者：
Kannouche, Patricia L.
影响因子：
5.3
作者：
Nougarède, R;Della Seta, F;Schwob, E
通讯作者：
Schwob, E