Pillaire Marie-Jeanne, Betous Rémy, Conti Chiara, Czaplicki Jerzy, Pasero Philippe, Bensimon Aaron, Cazaux Christophe, Hoffmann Jean-Sébastien
Group Instabilité génétique et cancer équipe labellisée par La ligue contre le cancer, Institut de Pharmacologie et de Biologie Structurale, Toulouse Cedex 4, France.
Cell Cycle. 2007 Feb 15;6(4):471-7. doi: 10.4161/cc.6.4.3857. Epub 2007 Feb 19.
There is rising evidence that cancer development is associated from its earliest stages with DNA replication stress, a major source of spontaneous genomic instability. However, the origin of these replication defects has remained unclear. We have investigated the consequences of upregulating error-prone DNA polymerases (pol) beta and kappa on chromosomal DNA replication. These enzymes are misregulated in different types of cancers and induce major chromosomal instabilities when overexpressed at low levels. Here, we have used DNA combing to show that a moderate overexpression of pol beta or pol kappa is sufficient to impede replication fork progression and to promote the activation of additional replication origins. Interestingly, alterations of the normal replication program induced by excess error-prone polymerases were not detected by the replication checkpoint. We therefore propose that upregulation of error-prone DNA polymerases induces a checkpoint-blind replication stress that contributes to genomic instability and to cancer development.
越来越多的证据表明，癌症从最早阶段就与DNA复制应激相关，而DNA复制应激是自发基因组不稳定的主要来源。然而，这些复制缺陷的起源仍不清楚。我们研究了上调易出错的DNA聚合酶（pol）β和κ对染色体DNA复制的影响。这些酶在不同类型的癌症中表达失调，当低水平过度表达时会诱导主要的染色体不稳定。在这里，我们使用DNA梳状技术表明，适度过度表达polβ或polκ足以阻碍复制叉的进展并促进额外复制起点的激活。有趣的是，复制检查点未检测到由过多易出错聚合酶诱导的正常复制程序的改变。因此，我们提出易出错的DNA聚合酶的上调会诱导一种检查点盲性复制应激，这种应激会导致基因组不稳定和癌症发展。
