Inhibition of ATM kinase rescues planarian regeneration after lethal radiation.
Inhibition of ATM kinase rescues planarian regeneration after lethal radiation.
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DOI：
10.15252/embr.202256112
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发表时间：
2023-05-04
期刊：
影响因子：
7.7
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中科院分区：
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当干细胞分裂时，它们获得的突变可以传递给子细胞。为了减轻潜在的有害结果，细胞激活DNA损伤反应（DDR）网络，该网络控制DNA损伤后的几种细胞结果，包括修复DNA或发生细胞凋亡。DDR的核心是三种PI3样激酶，包括Ataxia - telangiecasia Mutated （ATM）。我们在这里报道，在涡虫扁虫中敲除ATM使干细胞能够承受致死剂量的辐射，否则会导致细胞死亡。在这种情况下，干细胞绕过凋亡，复制其DNA，并通过同源重组介导的DNA修复恢复功能。尽管暴露在辐射中，atm基因敲低的动物仍能长期存活并再生新组织。这些作用独立于ATM的典型下游效应物p53而发生。总之，我们的研究结果表明，在涡虫中，ATM促进辐射诱导的细胞凋亡。这种急性的、依赖于ATM的细胞凋亡是动物长期存活的关键决定因素。因此，我们的研究结果表明，抑制这些生物体中的ATM可能有利于辐射后的细胞存活，而不会对干细胞行为产生明显影响。DNA损伤反应激酶ATM驱动辐射涡虫干细胞凋亡。atm的敲低可防止辐射后干细胞凋亡，并通过依赖同源重组使动物长期存活和再生。
As stem cells divide, they acquire mutations that can be passed on to daughter cells. To mitigate potentially deleterious outcomes, cells activate the DNA damage response (DDR) network, which governs several cellular outcomes following DNA damage, including repairing DNA or undergoing apoptosis. At the helm of the DDR are three PI3‐like kinases including Ataxia‐Telangiectasia Mutated (ATM). We report here that knockdown of ATM in planarian flatworms enables stem cells to withstand lethal doses of radiation which would otherwise induce cell death. In this context, stem cells circumvent apoptosis, replicate their DNA, and recover function using homologous recombination‐mediated DNA repair. Despite radiation exposure, atm knockdown animals survive long‐term and regenerate new tissues. These effects occur independently of ATM's canonical downstream effector p53. Together, our results demonstrate that in planarians, ATM promotes radiation‐induced apoptosis. This acute, ATM‐dependent apoptosis is a key determinant of long‐term animal survival. Our results suggest that inhibition of ATM in these organisms could, therefore, potentially favor cell survival after radiation without obvious effects on stem cell behavior. The DNA damage response kinase ATM drives stem cell apoptosis in radiated planarians. Knockdown of atm prevents stem cell apoptosis after radiation and enables long‐term animal survival and regeneration through a reliance on homologous recombination.