Bryant P E, Gray L J, Peresse N
Cancer Biology Group, Bute Medical School, University of St Andrews, St Andrews, Scotland.
Cytogenet Genome Res. 2004;104(1-4):65-71. doi: 10.1159/000077467.
The wide range of sensitivities of stimulated T-cells from different individuals to radiation-induced chromatid breakage indicates the involvement of several low penetrance genes that appear to link elevated chromatid breakage to cancer susceptibility. The mechanisms of chromatid breakage are not yet fully understood. However, evidence is accumulating that suggests chromatid breaks are not simply expanded DNA double-strand breaks (DSB). Three models of chromatid breakage are considered. The classical breakage-first and the Revell "exchange" models do not accord with current evidence. Therefore a derivative of Revell's model has been proposed whereby both spontaneous and radiation-induced chromatid breaks result from DSB signaling and rearrangement processes from within large looped chromatin domains. Examples of such rearrangements can be observed by harlequin staining whereby an exchange of strands occurs immediately adjacent to the break site. However, these interchromatid rearrangements comprise less than 20% of the total breaks. The rest are thought to result from intrachromatid rearrangements, including a very small proportion involving complete excision of a looped domain. Work is in progress with the aim of revealing these rearrangements, which may involve the formation of inversions adjacent to the break sites. It is postulated that the disappearance of chromatid breaks with time results from the completion of such rearrangements, rather than from the rejoining of DSB. Elevated frequencies of chromatid breaks occur in irradiated cells with defects in both nonhomologous end-joining (NHEJ) and homologous recombination (HR) pathways, however there is little evidence of a correlation between reduced DSB rejoining and disappearance of chromatid breaks. Moreover, at least one treatment which abrogates the disappearance of chromatid breaks with time leaves DSB rejoining unaffected. The I-SceI DSB system holds considerable promise for the elucidation of these mechanisms, although the break frequency is relatively low in the cell lines so far derived. Techniques to study and improve such systems are under way in different cell lines. Clearly, much remains to be done to clarify the mechanisms involved in chromatid breakage, but the experimental models are becoming available with which we can begin to answer some of the key questions.
来自不同个体的受刺激T细胞对辐射诱导的染色单体断裂具有广泛的敏感性，这表明有几个低外显率基因参与其中，这些基因似乎将染色单体断裂增加与癌症易感性联系起来。染色单体断裂的机制尚未完全了解。然而，越来越多的证据表明，染色单体断裂并非简单地是扩大的DNA双链断裂（DSB）。目前考虑了三种染色单体断裂模型。经典的先断裂模型和雷维尔的“交换”模型与当前证据不符。因此，有人提出了雷维尔模型的一个衍生模型，即自发和辐射诱导的染色单体断裂都是由大环状染色质结构域内的DSB信号传导和重排过程导致的。通过花斑染色可以观察到这种重排的例子，即断裂位点紧邻处发生链交换。然而，这些染色单体间重排占总断裂的比例不到20%。其余的被认为是由染色单体内重排导致的，包括极小比例涉及环状结构域完全切除的情况。目前正在开展工作以揭示这些重排，这可能涉及断裂位点附近倒位的形成。据推测，染色单体断裂随时间消失是由于此类重排的完成，而非DSB的重新连接。在非同源末端连接（NHEJ）和同源重组（HR）途径均有缺陷的受辐照细胞中，染色单体断裂频率升高，然而几乎没有证据表明DSB重新连接减少与染色单体断裂消失之间存在关联。此外，至少有一种消除染色单体断裂随时间消失现象的处理方法，并未影响DSB的重新连接。尽管到目前为止在衍生的细胞系中I-SceI DSB系统的断裂频率相对较低，但它在阐明这些机制方面具有很大潜力。不同细胞系正在开展研究和改进此类系统的技术。显然，要阐明染色单体断裂所涉及的机制仍有许多工作要做，但我们已经有了一些实验模型，可以开始回答一些关键问题。
