The Sister Chromatid Cohesion Pathway Suppresses Multiple Chromosome Gain and Chromosome Amplification
The Sister Chromatid Cohesion Pathway Suppresses Multiple Chromosome Gain and Chromosome Amplification
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DOI：
10.1534/genetics.113.159202
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发表时间：
2014-02-01
期刊：
影响因子：
3.3
通讯作者：
Resnick, Michael A.
中科院分区：
文献类型：
--
作者：
Covo, Shay;Puccia, Christopher M.;Resnick, Michael A.
导致非整倍体的染色体的获得或丢失可能是癌症和适应性进化的重要因素。虽然染色体获得在真核生物中是一种常见的事件，但关于其遗传控制的信息有限。在这里，我们测量了野生型酵母和姐妹染色单体凝聚力(SCC)受损菌株的染色体获得率。鳞状细胞癌通过粘附素复合体将新复制的染色单体拴在一起，直到后期。通过选择和鉴定由于金属硫蛋白基因CUP1拷贝增加而出现的抗铜菌落来测量染色体增益。尽管所有有缺陷的SCC二倍体菌株都表现出更高的染色体获得率，但它们之间的差异是15倍。在所有被检测的突变体中，粘附素复合体上的亚型突变导致的染色体获得率最高，而WPL1(鳞癌和染色体凝聚的重要调节因子)的破坏导致的染色体获得率增加最小。除了鳞状细胞癌中的缺陷，酵母细胞类型对染色体获得的贡献很大，纯合交配型二倍体的染色体获得率最高，杂合型交配型次之，单倍体最小。事实上，wpl1缺失的单倍体与野生型单倍体相比，在染色体获得率上没有任何差异。对铜抗性菌落的基因组分析表明，用于选择的驱动染色体可以被扩增到每个二倍体细胞5个以上的拷贝。此外，预期驱动染色体的增加通常伴随着少量其他染色体的获得。我们认为，虽然由于鳞状细胞癌功能障碍而获得的染色体可以通过基因失衡产生负面影响，但它也可以促进适应性变化的机会。在多细胞生物体中，这两个因素都可能导致包括癌症在内的躯体疾病。
Gain or loss of chromosomes resulting in aneuploidy can be important factors in cancer and adaptive evolution. Although chromosome gain is a frequent event in eukaryotes, there is limited information on its genetic control. Here we measured the rates of chromosome gain in wild-type yeast and sister chromatid cohesion (SCC) compromised strains. SCC tethers the newly replicated chromatids until anaphase via the cohesin complex. Chromosome gain was measured by selecting and characterizing copper-resistant colonies that emerged due to increased copies of the metallothionein gene CUP1. Although all defective SCC diploid strains exhibited increased rates of chromosome gain, there were 15-fold differences between them. Of all mutants examined, a hypomorphic mutation at the cohesin complex caused the highest rate of chromosome gain while disruption of WPL1, an important regulator of SCC and chromosome condensation, resulted in the smallest increase in chromosome gain. In addition to defects in SCC, yeast cell type contributed significantly to chromosome gain, with the greatest rates observed for homozygous mating-type diploids, followed by heterozygous mating type, and smallest in haploids. In fact, wpl1-deficient haploids did not show any difference in chromosome gain rates compared to wild-type haploids. Genomic analysis of copper-resistant colonies revealed that the driver chromosome for which selection was applied could be amplified to over five copies per diploid cell. In addition, an increase in the expected driver chromosome was often accompanied by a gain of a small number of other chromosomes. We suggest that while chromosome gain due to SCC malfunction can have negative effects through gene imbalance, it could also facilitate opportunities for adaptive changes. In multicellular organisms, both factors could lead to somatic diseases including cancer.