Tusell L, Soler D, Agostini M, Pampalona J, Genescà A
Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Cytogenet Genome Res. 2008;122(3-4):315-25. doi: 10.1159/000167818. Epub 2009 Jan 30.
Chromosomal instability is increasingly appreciated as a key component of tumorigenesis in humans. A combination of abnormal telomere shortening and cell-cycle checkpoint deficiency has been proposed as the initial lesions causing destabilizing chromatin bridges in proliferative cells. We examined the participation of the different types of end-to-end fusions in generating instable karyotypes in non-transformed human breast epithelial cells. We concluded that short dysfunctional telomeres represent an initiating substrate for post-replicative rejoining of sister chromatids and are likely to make an important contribution to the formation of chromosomal rearrangements and the amplification of chromosome arm segments in breast epithelial cells. We propose that there is a chronological order in the participation of the different types of end-to-end fusions in the generation of chromosomal instability. Thus, intrachromosomal post-replicative joining would proceed mainly in the early stages after overcoming growth arrest, when telomere dysfunction is limited and affects only one chromosome end in a cell. The absence of a second substrate for end joining will conduct the cell with the uncapped chromosome to replicate its DNA and fuse the uncapped sister chromatids after replication. Later, since telomeres shorten progressively with each DNA replication round, the uncapping will affect many more chromosome ends, and fusions between the uncapped ends from different chromosomes will be produced. While the fusion of sister chromatids will produce chromosome segment amplification and terminal deletions in the daughter cells, interchromosomal fusion will produce unbalanced rearrangements other than chromosome segment amplifications.
染色体不稳定日益被视为人类肿瘤发生的关键组成部分。异常端粒缩短和细胞周期检查点缺陷的组合被认为是导致增殖细胞中染色质桥不稳定的初始损伤。我们研究了不同类型的端到端融合在非转化人乳腺上皮细胞中产生不稳定核型的过程中的参与情况。我们得出结论，短的功能失调端粒是姐妹染色单体复制后重新连接的起始底物，并且可能对乳腺上皮细胞中染色体重排的形成和染色体臂段的扩增做出重要贡献。我们提出，在染色体不稳定的产生过程中，不同类型的端到端融合的参与存在时间顺序。因此，染色体内复制后连接主要在克服生长停滞后的早期阶段进行，此时端粒功能障碍有限，仅影响细胞中的一个染色体末端。缺乏用于末端连接的第二种底物将导致带有未加帽染色体的细胞复制其DNA并在复制后融合未加帽的姐妹染色单体。后来，由于端粒随着每个DNA复制轮次逐渐缩短，未加帽将影响更多的染色体末端，并产生来自不同染色体的未加帽末端之间的融合。虽然姐妹染色单体的融合将在子细胞中产生染色体片段扩增和末端缺失，但染色体间融合将产生除染色体片段扩增之外的不平衡重排。
