Checkpoint non-fidelity induces a complex landscape of lineage fitness after DNA damage
Checkpoint non-fidelity induces a complex landscape of lineage fitness after DNA damage
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检查点不保真会在 DNA 损伤后引发复杂的谱系适应性景观
DOI：
10.1101/431486
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Campbell C
中科院分区：
文献类型：
--
作者：
Campbell C
增殖的哺乳动物细胞中的DNA损伤通过监测损伤和调节细胞周期进程、DNA修复和命运决定的检查点导致死亡、衰老或持续存活。细胞周期检查点通过防止增殖突变细胞的产生，特别是通过阻断DNA损伤进入复制和有丝分裂来促进肿瘤抑制。虽然检查点非保真度允许细胞将基因组畸变带入随后的细胞周期阶段，但其对受损细胞后代谱系的长期影响仍然很难表征。设计基于显微镜的谱系追踪方法，我们出乎意料地证明，携带疏忽检查点的单个活细胞的瞬时DNA损伤在从初始损伤中去除的后代中诱导异质细胞命运结果。在短暂受损的细胞经历最初的停滞后，没有明显细胞周期异常的后代细胞对以看似随机的方式分裂或死亡。短暂受损细胞的后代可能会在几代之后死亡，从而产生相当大的谱系适应性变异，从而促进在诱变环境中的整体持久性。受损细胞的后代经常形成微核，激活免疫原性信号。我们的研究结果揭示了以前未被认识到的细胞DNA损伤的异质性效应，这些效应在后代细胞中很久以后才表现出来。我们认为，这些异质性后代细胞命运的反应可能在生理上发挥作用，以确保消除和免疫清除受损的细胞谱系，但在病理上，可能使细胞的生存期延长轴承诱变损伤。
DNA damage in proliferating mammalian cells causes death, senescence or continued survival, via checkpoints that monitor damage and regulate cell cycle progression, DNA repair and fate determination. Cell cycle checkpoints facilitate tumour suppression by preventing the generation of proliferating mutated cells, particularly by blocking passage of DNA lesions into replication and mitosis. While checkpoint non-fidelity permits cells to carry genomic aberrations into subsequent cell cycle phases, its long-term consequences on lineages descendant from damaged cells remains poorly characterised. Devising methods for microscopy-based lineage tracing, we unexpectedly demonstrate that transient DNA damage to single living cells bearing a negligent checkpoint induces heterogenous cell-fate outcomes in their descendant generations removed from the initial insult. After transiently damaged cells undergo an initial arrest, pairs of descendant cells without obvious cell-cycle abnormalities either divide or die in a seemingly stochastic way. Progeny of transiently damaged cells may die generations afterwards, creating considerable variability of lineage fitness that promotes overall persistence in a mutagenic environment. Descendants of damaged cells frequently form micronuclei, activating immunogenic signalling. Our findings reveal previously unrecognized, heterogenous effects of cellular DNA damage that manifest long afterwards in descendant cells. We suggest that these heterogenous descendant cell-fate responses may function physiologically to ensure the elimination and immune clearance of damaged cell lineages, but pathologically, may enable the prolonged survival of cells bearing mutagenic damage.
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