ATM and KAT5 safeguard replicating chromatin against formaldehyde damage.
ATM and KAT5 safeguard replicating chromatin against formaldehyde damage.
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DOI：
10.1093/nar/gkv957
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发表时间：
2016-01-08
影响因子：
14.9
通讯作者：
Zhitkovich A
中科院分区：
文献类型：
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作者：
Ortega-Atienza S;Wong VC;DeLoughery Z;Luczak MW;Zhitkovich A
许多致癌物会损害染色质的 DNA 和蛋白质成分，目前尚不清楚细胞如何应对这种复合损伤。我们检查了主要 DNA 损伤响应激酶 ATM 的激活以及甲醛 (FA) 形成组蛋白加合物和复制阻断 DNA-蛋白质交联 (DPC) 造成的 DNA 双链断裂 (DSB) 的情况。我们发现低 FA 剂量会导致人体细胞中 ATM 信号强烈而快速地激活，该信号不依赖于 ATR，且仅限于 S 期。高 FA 剂量通过共价二聚化和形成更大的交联来灭活 ATM。相对于 DSB 诱导剂，FA 诱导的 ATM 信号显示出较高的 CHK2 磷酸化，但磷酸化 KAP1 较低。在 ATM 激活的主波期间，DPC 的复制阻塞不会产生损坏的分叉或可检测到的 DSB 量，这不需要 MRE11。染色质监控 KAT5 (Tip60) 乙酰转移酶负责 FA 乙酰化和激活 ATM。 KAT5 和 ATM 对于触发 S 期检查点同样重要，并且 ATM 信号传导促进低剂量 FA 后正常人体细胞的恢复。我们的结果揭示了 KAT5-ATM 轴在保护复制染色质免受内源性致癌物 FA 损伤方面的主要作用。
Many carcinogens damage both DNA and protein constituents of chromatin, and it is unclear how cells respond to this compound injury. We examined activation of the main DNA damage-responsive kinase ATM and formation of DNA double-strand breaks (DSB) by formaldehyde (FA) that forms histone adducts and replication-blocking DNA-protein crosslinks (DPC). We found that low FA doses caused a strong and rapid activation of ATM signaling in human cells, which was ATR-independent and restricted to S-phase. High FA doses inactivated ATM via its covalent dimerization and formation of larger crosslinks. FA-induced ATM signaling showed higher CHK2 phosphorylation but much lower phospho-KAP1 relative to DSB inducers. Replication blockage by DPC did not produce damaged forks or detectable amounts of DSB during the main wave of ATM activation, which did not require MRE11. Chromatin-monitoring KAT5 (Tip60) acetyltransferase was responsible for acetylation and activation of ATM by FA. KAT5 and ATM were equally important for triggering of intra-S-phase checkpoint and ATM signaling promoted recovery of normal human cells after low-dose FA. Our results revealed a major role of the KAT5-ATM axis in protection of replicating chromatin against damage by the endogenous carcinogen FA.