ATR suppresses apoptosis after UVB irradiation by controlling both translesion synthesis and alternative tolerance pathways
ATR suppresses apoptosis after UVB irradiation by controlling both translesion synthesis and alternative tolerance pathways
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DOI：
10.1242/jcs.161596
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发表时间：
2015-01-01
影响因子：
4
通讯作者：
Menck, Carlos F. M.
中科院分区：
文献类型：
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作者：
Andrade-Lima, Leonardo C.;Andrade, Luciana N.;Menck, Carlos F. M.
紫外线（UV）光可以由于在DNA中形成大的损伤而使复制叉停滞。通过跨损伤DNA合成发生跨越这些阻断损伤的复制，并且细胞激活对UV的ATR损伤反应。然而，目前尚不清楚病变旁路是否需要复制检查点，因为ATR是不必要的PCNA泛素化。我们观察到，ATR敲低siRNA增加复制压力，促进早期诱导细胞凋亡后，UVB照射SV 40永生化的人细胞，包括细胞从XP-V和XP-C患者。XP-V细胞通过沉默进一步敏化，表明尽管ATR控制，DNA聚合酶eta（eta）仍然保持活性。然而，在UVB照射后，ATR耗尽的细胞无法实现有丝分裂，正如在DNA检查点控制丧失后所预期的那样。因此，ATR还调节复制停滞恢复UVB诱导的损伤后，独立于Pol eta，在SV 40永生化细胞系。ATR介导的DNA损伤反应调节复制和不同的耐受途径，在这些细胞中，ATR耗竭诱导复制灾难，这有助于解释ATR抑制对UVB诱导的致癌作用的保护潜力。
Ultraviolet (UV) light can stall replication forks owing to the formation of bulky lesions in the DNA. Replication across these blocking lesions occurs through translesion DNA synthesis, and cells activate the ATR damage responses to UV. However, it remains unclear whether lesion bypass requires the replication checkpoint because ATR is not necessary for PCNA ubiquitylation. We observed that ATR knockdown by siRNA increased replication stress and promoted early induction of apoptosis following UVB irradiation in SV40-immortalized human cells, including cells from XP-V and XP-C patients. XP-V cells were further sensitized by the silencing, indicating that DNA polymerase eta ( eta) remains active despite ATR control. However, following UVB irradiation, ATR-depleted cells were unable to achieve mitosis, as would be expected after the loss of a DNA checkpoint control. Thus, ATR also regulates replication arrest recovery following UVB-induced damage, independently of Pol eta, in SV40-immortalized cell lines. The ATR-mediated DNA damage response regulates replication and different tolerance pathways, and in these cells, ATR depletion induces replication catastrophe, which contributes to explain the potential of ATR inhibition to protect against UVB-induced carcinogenesis.