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首页> 外文期刊>DNA repair >Cooperative responses of DNA-damage-activated protein kinases ATR and ATM and DNA translesion polymerases to replication-blocking DNA damage in a stem-cell niche.
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Cooperative responses of DNA-damage-activated protein kinases ATR and ATM and DNA translesion polymerases to replication-blocking DNA damage in a stem-cell niche.

机译：DNA损伤激活蛋白激酶ATR和ATM以及DNA转移损伤聚合酶对干细胞环境中复制阻断DNA损伤的协同反应。

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摘要

Conserved DNA-damage responses (DDRs) efficiently cope with replication blocks and double-strand breaks (DSBs) in cultured eukaryotic cells; DDRs in tissues remain poorly understood. DDR-inactivating mutations lethal in animals are tolerated in Arabidopsis, whose root meristem provides a powerful stem-cell-niche model. We imaged UVB-induced death of specific meristem cells in single and double Arabidopsis mutants to elucidate cooperation among DNA translesion synthesis (TLS) polymerases (Poleta, Polzeta) and DNA-damage-activated protein kinases (ATR, ATM). Death was 100-fold higher in stem and progenitor (StPr) cells than in transiently amplifying cells. Quantitative analyses of dose-response plots showed that Poleta and Polzeta act redundantly to tolerate replication blocks and that Polzeta-mediated TLS requires ATR. Deficient TLS resulted in ATM-signaled death, which first appeared 10-14h post-UVB. Although ssDNA downstream of blocks was likely cleaved into DSBs throughout S phase, death pathways appeared to initiate late in S. In atm mutants death appeared much later, likely signaled by a slow ATR-dependent pathway. To bypass replication blocks, tissues may use TLS rather than error-free pathways that could generate genomic aberrations. Dynamic balances among ATR and ATM death-avoidance and death-signaling functions determine how many DSB-burdened StPr cells are killed. Their replacement by less-burdened quiescent-center cells then restores growth homeostasis.
机译：保守的DNA损伤反应（DDR）可有效应对培养的真核细胞中的复制阻滞和双链断裂（DSB）。组织中的DDR仍然知之甚少。在拟南芥中可以耐受在动物中致死的DDR失活突变，其根分生组织提供了强大的干细胞生态位模型。我们对单个和两个拟南芥突变体中特定分生组织细胞的UVB诱导的死亡进行了成像，以阐明DNA损伤合成（TLS）聚合酶（Poleta，Polzeta）和DNA损伤激活的蛋白激酶（ATR，ATM）之间的合作。干细胞和祖细胞（StPr）的死亡比瞬时扩增细胞高100倍。剂量-反应图的定量分析表明，Poleta和Polzeta可以冗余地耐受复制阻滞，并且Polzeta介导的TLS需要ATR。 TLS不足会导致ATM信号死亡，这首先在UVB后10-14小时出现。尽管下游的ssDNA可能在整个S期均被切割成DSB，但死亡途径似乎在S期晚期开始。在atm突变体中，死亡出现的时间要晚得多，这可能是由ATR依赖性途径缓慢引起的。为了绕过复制块，组织可以使用TLS而不是可能产生基因组畸变的无错误途径。 ATR和ATM避免死亡和死亡信号传递功能之间的动态平衡决定了杀死多少DSB负担的StPr细胞。然后用负担减轻的静态中心细胞替代它们，从而恢复生长稳态。

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