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咖啡因可以越过裂殖酵母中的S-M检验点。

Caffeine can override the S-M checkpoint in fission yeast.

作者信息

Wang S W, Norbury C, Harris A L, Toda T

机构信息

Imperial Cancer Research Fund, Cell Regulation Laboratory, PO Box 123, Lincoln's Inn Fields, London WC2 A3P, UK.

出版信息

J Cell Sci. 1999 Mar;112 ( Pt 6):927-37. doi: 10.1242/jcs.112.6.927.

Abstract

The replication checkpoint (or 'S-M checkpoint') control prevents progression into mitosis when DNA replication is incomplete. Caffeine has been known for some time to have the capacity to override the S-M checkpoint in animal cells. We show here that caffeine also disrupts the S-M checkpoint in the fission yeast Schizosaccharomyces pombe. By contrast, no comparable effects of caffeine on the S. pombe DNA damage checkpoint were seen. S. pombe cells arrested in early S phase and then exposed to caffeine lost viability rapidly as they attempted to enter mitosis, which was accompanied by tyrosine dephosphorylation of Cdc2. Despite this, the caffeine-induced loss of viability was not blocked in a temperature-sensitive cdc2 mutant incubated at the restrictive temperature, although catastrophic mitosis was prevented under these conditions. This suggests that, in addition to S-M checkpoint control, a caffeine-sensitive function may be important for maintenance of cell viability during S phase arrest. The lethality of a combination of caffeine with the DNA replication inhibitor hydroxyurea was suppressed by overexpression of Cds1 or Chk1, protein kinases previously implicated in S-M checkpoint control and recovery from S phase arrest. In addition, the same combination of drugs was specifically tolerated in cells overexpressing either of two novel S. pombe genes isolated in a cDNA library screen. These findings should allow further molecular investigation of the regulation of S phase arrest, and may provide a useful system with which to identify novel drugs that specifically abrogate the checkpoint control.

摘要

复制检查点(或“S-M检查点”)控制可防止在DNA复制不完全时进入有丝分裂。一段时间以来,人们已知咖啡因有能力在动物细胞中绕过S-M检查点。我们在此表明,咖啡因也会破坏裂殖酵母粟酒裂殖酵母中的S-M检查点。相比之下,未观察到咖啡因对粟酒裂殖酵母DNA损伤检查点有类似影响。在S期早期停滞的粟酒裂殖酵母细胞,在试图进入有丝分裂时接触咖啡因后会迅速丧失活力,这伴随着Cdc2的酪氨酸去磷酸化。尽管如此,在限制温度下培养的温度敏感型cdc2突变体中,咖啡因诱导的活力丧失并未被阻断,尽管在这些条件下可防止灾难性有丝分裂。这表明,除了S-M检查点控制外,一种对咖啡因敏感的功能对于在S期停滞期间维持细胞活力可能很重要。咖啡因与DNA复制抑制剂羟基脲联合使用的致死性可通过过表达Cds1或Chk1来抑制,这两种蛋白激酶先前与S-M检查点控制及从S期停滞中恢复有关。此外,在cDNA文库筛选中分离出的两个粟酒裂殖酵母新基因中,任何一个过表达的细胞都能特异性耐受相同的药物组合。这些发现应有助于对S期停滞调控进行进一步的分子研究,并可能提供一个有用的系统来鉴定特异性消除检查点控制的新型药物。

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