The role of mechanistic factors in promoting chromosomal translocations found in lymphoid and other cancers.
The role of mechanistic factors in promoting chromosomal translocations found in lymphoid and other cancers.
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DOI：
10.1016/s0065-2776(10)06004-9
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发表时间：
2010
影响因子：
--
通讯作者：
Alt, Frederick W.
中科院分区：
文献类型：
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作者：
Zhang, Yu;Gostissa, Monica;Hildebrand, Dominic G.;Becker, Michael S.;Boboila, Cristian;Chiarle, Roberto;Lewis, Susanna;Alt, Frederick W.
反复出现的染色体异常，特别是染色体易位，与某些亚型的白血病、淋巴瘤和实体瘤密切相关。特定易位或相关基因组改变的出现可能是疾病预后的重要指标，在某些情况下，某些易位可能表明适当的治疗方案。到目前为止，我们关于染色体易位的大部分知识都来自于对某些癌症中发现的高度选择性的反复易位的描述。直到最近，促进或抑制染色体易位的机制，特别是那些负责启动染色体易位的机制，还没有被解决。为了发生易位，两个不同的染色体位点必须断裂，结合在一起(突触)并连接在一起。在这里，我们讨论了影响染色体易位启动的过程和途径的最新发现，包括由一般因素或在淋巴细胞特异性V(D)J和IgH类开关重组过程的背景下产生DNA双链断裂(DSB)。我们还讨论了DSB在间期核中的空间邻近性对不同染色体上的DSB如何恰好连接的作用。此外，我们还讨论了DNA DSB的反应及其在识别和连接染色体DSB以防止易位中的作用，以及经典的和替代的DSB末端连接途径在抑制或促进易位中的潜在作用。最后，我们讨论了长程调控元件，如3‘IgH增强子复合体，在促进淋巴瘤中常见的某些易位的表达方面的潜在作用，从而促进它们在肿瘤中的频繁出现。
Recurrent chromosomal abnormalities, especially chromosomal translocations, are strongly associated with certain subtypes of leukemia, lymphoma and solid tumors. The appearance of particular translocations or associated genomic alterations can be important indicators of disease prognosis, and in some cases, certain translocations may indicate appropriate therapy protocols. To date, most of our knowledge about chromosomal translocations has derived from characterization of the highly selected recurrent translocations found in certain cancers. Until recently, mechanisms that promote or suppress chromosomal translocations, in particular, those responsible for their initiation, have not been addressed. For translocations to occur, two distinct chromosomal loci must be broken, brought together (synapsed) and joined. Here, we discuss recent findings on processes and pathways that influence the initiation of chromosomal translocations, including the generation fo DNA double strand breaks (DSBs) by general factors or in the context of the Lymphocyte-specific V(D)J and IgH class-switch recombination processes. We also discuss the role of spatial proximity of DSBs in the interphase nucleus with respect to how DSBs on different chromosomes are justaposed for joining. In addition, we discuss the DNA DSB response and its role in recognizing and tethering chromosomal DSBs to prevent translocations, as well as potential roles of the classical and alternative DSB end-joining pathways in suppressing or promoting translocations. Finally, we discuss the potential roles of long range regulatory elements, such as the 3’IgH enhancer complex, in promoting the expression of certain translocations that are frequent in lymphomas and, thereby, contributing to their frequent appearance in tumors.