Drosophila ATM and ATR have distinct activities in the regulation of meiotic DNA damage and repair.
Drosophila ATM and ATR have distinct activities in the regulation of meiotic DNA damage and repair.
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DOI：
10.1083/jcb.201104121
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发表时间：
2011-10-31
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影响因子：
--
通讯作者：
McKim KS
中科院分区：
文献类型：
--
作者：
Joyce EF;Pedersen M;Tiong S;White-Brown SK;Paul A;Campbell SD;McKim KS
ATM 和 ATR 在减数分裂 DSB 修复中表现出不同的活性，因此 ATM 在 DNA 损伤修复和对程序性双链断裂的负反馈控制中发挥作用，而 ATR 是检查点活性所必需的。共济失调毛细血管扩张突变 (ATM) 和共济失调毛细血管扩张相关 (ATR) 激酶是细胞对双链断裂 (DSB) 反应的保守调节因子。然而，在减数分裂期间，这些激酶在 DSB 修复和脱氧核糖核酸 (DNA) 损伤检查点中的功能尚不清楚。在本文中，我们证明 ATM 和 ATR 在果蝇减数分裂 DSB 的修复中具有独特的作用。 ATR 突变体分析表明，它是检查点活性所必需的，而 ATM 可能不是。两种激酶都会磷酸化 H2AV (γ-H2AV)，并且利用其作为 ATM/ATR 活性的报告基因，我们发现 DSB 修复反应在 DNA 损伤部位具有惊人的动态性。 γ-H2AV 不断交换，需要在断裂位点进行新的磷酸化，直到修复完成。然而，最令人惊讶的是，在没有 ATM 的情况下，γ-H2AV 焦点的数量显着增加，但 ATR 没有增加，这表明 DSB 的数量增加了。因此，我们得出结论，ATM 主要是减数分裂 DSB 修复反应所必需的，其中包括 DNA 损伤修复功能和减数分裂期间对编程 DSB 水平的负反馈控制。
ATM and ATR display distinct activities in meiotic DSB repair, such that ATM functions in DNA damage repair and negative feedback control over programmed double strand breaks, whereas ATR is required for checkpoint activity. Ataxia telangiectasia–mutated (ATM) and ataxia telangiectasia–related (ATR) kinases are conserved regulators of cellular responses to double strand breaks (DSBs). During meiosis, however, the functions of these kinases in DSB repair and the deoxyribonucleic acid (DNA) damage checkpoint are unclear. In this paper, we show that ATM and ATR have unique roles in the repair of meiotic DSBs in Drosophila melanogaster. ATR mutant analysis indicated that it is required for checkpoint activity, whereas ATM may not be. Both kinases phosphorylate H2AV (γ-H2AV), and, using this as a reporter for ATM/ATR activity, we found that the DSB repair response is surprisingly dynamic at the site of DNA damage. γ-H2AV is continuously exchanged, requiring new phosphorylation at the break site until repair is completed. However, most surprising is that the number of γ-H2AV foci is dramatically increased in the absence of ATM, but not ATR, suggesting that the number of DSBs is increased. Thus, we conclude that ATM is primarily required for the meiotic DSB repair response, which includes functions in DNA damage repair and negative feedback control over the level of programmed DSBs during meiosis.
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