Redundancy between nucleases required for homologous recombination promotes PARP inhibitor resistance in the eukaryotic model organism Dictyostelium.
Redundancy between nucleases required for homologous recombination promotes PARP inhibitor resistance in the eukaryotic model organism Dictyostelium.
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DOI：
10.1093/nar/gkx639
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发表时间：
2017-09-29
影响因子：
14.9
通讯作者：
Lakin ND
中科院分区：
文献类型：
--
作者：
Kolb AL;Gunn AR;Lakin ND
ADP-核糖基转移酶促进DNA单链断裂的修复，并且聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）对该途径的破坏对同源重组（HR）缺陷的细胞是有毒的。在这里，我们表明，这种关系是保守的，在简单的真核生物Dictyosteopathy和利用这种生物体来定义机制，驱动电阻的HR缺陷细胞PARPi。在外切核酸酶I（HR的关键因子）中被破坏的网囊藻细胞对PARPi敏感。exo 1的缺失阻止了由PARPi诱导的Rad 51在染色质中的积累，导致DNA损伤通过非同源末端连接（NHEJ）修复而被引导。NHEJ的失活抑制了exo 1 −细胞对PARPi的敏感性，表明该途径驱动了合成致死性，并且在其缺失的情况下，替代修复机制促进了细胞存活。这种耐药性与替代NHEJ无关，而是通过HR的重新激活来实现。此外，Mre 11抑制剂恢复了dnapkcs-exo 1-细胞对PARPi的敏感性，这表明启动HR的核酸酶之间的冗余可以驱动PARPi耐药性。这些数据提供了HR缺陷细胞中PARPi抗性机制的信息，并将Dictyosteoprotein作为表征这些途径的方便遗传模型。
ADP-ribosyltransferases promote repair of DNA single strand breaks and disruption of this pathway by Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) is toxic to cells with defects in homologous recombination (HR). Here, we show that this relationship is conserved in the simple eukaryote Dictyostelium and exploit this organism to define mechanisms that drive resistance of the HR-deficient cells to PARPi. Dictyostelium cells disrupted in exonuclease I, a critical factor for HR, are sensitive to PARPi. Deletion of exo1 prevents the accumulation of Rad51 in chromatin induced by PARPi, resulting in DNA damage being channelled through repair by non-homologous end-joining (NHEJ). Inactivation of NHEJ supresses the sensitivity of exo1− cells to PARPi, indicating this pathway drives synthetic lethality and that in its absence alternative repair mechanisms promote cell survival. This resistance is independent of alternate-NHEJ and is instead achieved by re-activation of HR. Moreover, inhibitors of Mre11 restore sensitivity of dnapkcs−exo1− cells to PARPi, indicating redundancy between nucleases that initiate HR can drive PARPi resistance. These data inform on mechanism of PARPi resistance in HR-deficient cells and present Dictyostelium as a convenient genetic model to characterize these pathways.
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影响因子：
14.9
作者：
Faix, J;Kreppel, L;Kimmel, AR
通讯作者：
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影响因子：
4
作者：
Gunn AR;Banos-Pinero B;Paschke P;Sanchez-Pulido L;Ariza A;Day J;Emrich M;Leys D;Ponting CP;Ahel I;Lakin ND
通讯作者：
Lakin ND
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通讯作者：
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作者：
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通讯作者：
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由 53BP1-RIF1 和 BRCA1-CtIP 组成的细胞周期依赖性调节回路控制 DNA 修复途径的选择。
影响因子：
16
作者：
Escribano-Diaz, Cristina;Orthwein, Alexandre;Durocher, Daniel
通讯作者：
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