Department of Biological Sciences & Institute of Molecular Biology and Genetics, Seoul National University, Korea.
Department of Bioengineering, School of Life Sciences, Ulsan National Institute of Science and Technology, Korea.
FEBS J. 2021 Oct;288(20):5925-5942. doi: 10.1111/febs.15912. Epub 2021 May 21.
Accurate chromosomal segregation during mitosis is regulated by the spindle assembly checkpoint (SAC). SAC failure results in aneuploidy, a hallmark of cancer. However, many studies have suggested that aneuploidy alone is not oncogenic. We have reported that BubR1 acetylation deficiency in mice (K243R/+) caused spontaneous tumorigenesis via weakened SAC signaling and unstable chromosome-spindle attachment, resulting in massive chromosomal mis-segregation. In addition to aneuploidy, cells derived from K243R/+ mice exhibited moderate genetic instability and chromosomal translocation. Here, we investigated how the loss of BubR1 acetylation led to genetic instability and chromosomal rearrangement. To rescue all chromosomal abnormalities generated by the loss of BubR1 acetylation during development, K243R/+ mice were crossed with p53-deficient mice. Genome-wide sequencing and spectral karyotyping of tumors derived from these double-mutant mice revealed that BubR1 acetylation deficiency was associated with complex chromosomal rearrangements, including Robertsonian-like whole-arm translocations. By analyzing the telomeres and centromeres in metaphase chromosome spreads, we found that BubR1 acetylation deficiency increased the collapse of stalled replication forks, commonly referred to as replication stress, and led to DNA damage and chromosomal rearrangements. BubR1 mutations that are critical in interacting with PCAF acetyltransferase and acetylating K250, L249F and A251P, were found from human cancers. Furthermore, a subset of human cancer cells exhibiting whole-arm translocation also displayed defects in BubR1 acetylation, supporting that defects in BubR1 acetylation in mitosis contributes to tumorigenesis. Collectively, loss of BubR1 acetylation provokes replication stress, particularly at the telomeres, leading to genetic instability and chromosomal rearrangement.
在有丝分裂过程中，染色体的准确分离受纺锤体组装检查点（SAC）调控。SAC 故障会导致非整倍体，这是非典型性肿瘤的特征之一。然而，许多研究表明，非整倍体本身并不致癌。我们曾报道过，在小鼠中（K243R/+)BubR1 乙酰化缺陷导致自发性肿瘤形成，这是由于 SAC 信号减弱和染色体-纺锤体连接不稳定，导致大量染色体错误分离。除了非整倍体外，源自 K243R/+ 小鼠的细胞还表现出中等程度的遗传不稳定性和染色体易位。在这里，我们研究了 BubR1 乙酰化缺失如何导致遗传不稳定性和染色体重排。为了挽救在发育过程中因 BubR1 乙酰化缺失而产生的所有染色体异常，我们将 K243R/+ 小鼠与 p53 缺失小鼠进行杂交。对源自这些双突变小鼠的肿瘤进行全基因组测序和光谱核型分析表明，BubR1 乙酰化缺失与复杂的染色体重排有关，包括罗伯逊易位样全臂易位。通过分析中期染色体扩散中的端粒和着丝粒，我们发现 BubR1 乙酰化缺失会增加停滞复制叉的崩溃，通常称为复制应激，从而导致 DNA 损伤和染色体重排。在人类癌症中发现了与 PCAF 乙酰转移酶相互作用并乙酰化 K250、L249F 和 A251P 的关键 BubR1 突变。此外，表现出全臂易位的一部分人类癌细胞也显示出 BubR1 乙酰化缺陷，这支持了有丝分裂中 BubR1 乙酰化缺陷会导致肿瘤发生的观点。总之，BubR1 乙酰化缺失会引发复制应激，尤其是在端粒处，从而导致遗传不稳定性和染色体重排。
