Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, MN, USA.
Adv Exp Med Biol. 2018;1044:89-112. doi: 10.1007/978-981-13-0593-1_7.
Chromosomal translocations are now well understood to not only constitute signature molecular markers for certain human cancers but often also to be causative in the genesis of that tumor. Despite the obvious importance of such events, the molecular mechanism of chromosomal translocations in human cells remains poorly understood. Part of the explanation for this dearth of knowledge is due to the complexity of the reaction and the need to archaeologically work backwards from the final product (a translocation) to the original unrearranged chromosomes to infer mechanism. Although not definitive, these studies have indicated that the aberrant usage of endogenous DNA repair pathways likely lies at the heart of the problem. An equally obfuscating aspect of this field, however, has also originated from the unfortunate species-specific differences that appear to exist in the relevant model systems that have been utilized to investigate this process. Specifically, yeast and murine systems (which are often used by basic science investigators) rely on different DNA repair pathways to promote chromosomal translocations than human somatic cells. In this chapter, we will review some of the basic concepts of chromosomal translocations and the DNA repair systems thought to be responsible for their genesis with an emphasis on underscoring the differences between other species and human cells. In addition, we will focus on a specific subset of translocations that involve the very end of a chromosome (a telomere). A better understanding of the relationship between DNA repair pathways and chromosomal translocations is guaranteed to lead to improved therapeutic treatments for cancer.
染色体易位不仅是某些人类癌症的标志性分子标志物，而且常常也是肿瘤发生的原因。尽管这些事件非常重要，但人类细胞中染色体易位的分子机制仍了解甚少。造成这种知识匮乏的部分原因是由于反应的复杂性以及需要从最终产物（易位）回溯到原始未重排的染色体，以推断机制。尽管这些研究尚不能确定，但它们表明内源性 DNA 修复途径的异常使用可能是问题的核心。然而，该领域同样令人困惑的一个方面也源于在用于研究该过程的相关模型系统中似乎存在的不幸的种间差异。具体来说，酵母和鼠类系统（基础科学研究人员经常使用）依赖于不同的 DNA 修复途径来促进染色体易位，而不同于人类体细胞。在本章中，我们将回顾一些染色体易位的基本概念以及被认为与易位发生有关的 DNA 修复系统，并重点强调其他物种与人类细胞之间的差异。此外，我们将重点关注涉及染色体末端（端粒）的特定易位亚类。更好地理解 DNA 修复途径与染色体易位之间的关系，必将导致癌症治疗方法的改善。
