Warmerdam Daniël O, van den Berg Jeroen, Medema René H
Division of Cell Biology I, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Division of Cell Biology I, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Cell Rep. 2016 Mar 22;14(11):2519-27. doi: 10.1016/j.celrep.2016.02.048. Epub 2016 Mar 10.
rDNA repeats constitute the most heavily transcribed region in the human genome. Tumors frequently display elevated levels of recombination in rDNA, indicating that the repeats are a liability to the genomic integrity of a cell. However, little is known about how cells deal with DNA double-stranded breaks in rDNA. Using selective endonucleases, we show that human cells are highly sensitive to breaks in 45S but not the 5S rDNA repeats. We find that homologous recombination inhibits repair of breaks in 45S rDNA, and this results in repeat loss. We identify the structural maintenance of chromosomes protein 5 (SMC5) as contributing to recombination-mediated repair of rDNA breaks. Together, our data demonstrate that SMC5-mediated recombination can lead to error-prone repair of 45S rDNA repeats, resulting in their loss and thereby reducing cellular viability.
核糖体DNA重复序列构成了人类基因组中转录最活跃的区域。肿瘤细胞中核糖体DNA的重组水平常常升高，这表明这些重复序列对细胞的基因组完整性是一种负担。然而，对于细胞如何处理核糖体DNA中的DNA双链断裂，我们知之甚少。通过使用选择性核酸内切酶，我们发现人类细胞对45S核糖体DNA重复序列中的断裂高度敏感，但对5S核糖体DNA重复序列中的断裂不敏感。我们发现同源重组会抑制45S核糖体DNA中断裂的修复，从而导致重复序列丢失。我们确定染色体结构维持蛋白5（SMC5）有助于核糖体DNA断裂的重组介导修复。总之，我们的数据表明，SMC5介导的重组会导致45S核糖体DNA重复序列的易错修复，导致其丢失，从而降低细胞活力。
