p53 accumulates but is functionally impaired when DNA synthesis is blocked
p53 accumulates but is functionally impaired when DNA synthesis is blocked
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DOI：
10.1073/pnas.021282898
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发表时间：
2001-01-30
影响因子：
11.1
通讯作者：
Prives, C
中科院分区：
文献类型：
--
作者：
Gottifredi, V;Shieh, SY;Prives, C
P53是诱导伽玛射线照射后G(1)和/或G(2)不可逆性停滞所必需的，而阻断DNA复制则导致P53非依赖的S期停滞。我们研究了当DNA合成被羟基脲(HU)或APHICOIN阻断时，或当DNA被伽马IR损伤时，对P53的反应。与伽马IR类似，DNA合成受阻会诱导高水平的磷酸化核P53。令人惊讶的是，当DNA复制被阻止时，几个(但不是所有)由伽马IR快速诱导的P53转录靶点被弱诱导或不诱导。此外，P53对伽马IR的反应被HU或aphidiclin预处理细胞所抑制，这表明阻止DNA复制阻止了P53作为转录因子的完全活性。HU诱导的P53的稳定既不需要有功能的ATM(共济失调毛细血管扩张突变)，也不干扰依赖于IR的ATM激酶的激活。因此，停滞不前的复制分叉激活了修改和稳定P53的激酶，但作用于ATM下游以削弱P53的转录活性。讨论了这种新的P53调控的分支。
p53 is required for the induction of a G(1) and/or G(2) irreversible arrest after gamma irradiation (IR), whereas blocked DNA replication causes a p53-independent S-phase arrest. We have examined the response to p53 when DNA synthesis is blocked by hydroxyurea (HU) or aphidicolin or when DNA is damaged by gamma IR. Similarly to gamma IR, blocked DNA synthesis induces high levels of phosphorylated nuclear p53. Surprisingly, several (but not all) p53 transcriptional targets that are rapidly induced by gamma IR are weakly or not induced when DNA replication is blocked. Moreover, the p53 response to gamma IR is inhibited by pretreatment of cells with HU or aphidicolin, suggesting that blocked DNA replication prevents p53 from being fully active as a transcription factor. HU-induced stabilization of p53 neither requires functional ATM (ataxia telangiectasia mutated), nor interferes with the gamma IR-dependent activation of the ATM kinase. Thus, stalled replication forks activate kinases that modify and stabilize p53, yet act downstream of ATM to impair p53 transcriptional activity. The ramifications of this novel regulation of p53 are discussed.