Yoon Jung Hwan, Eun Jung Woo, Ashktorab Hassan, Smoot Duane T, Kim Jeong Kyu, Nam Suk Woo, Park Won Sang
Department of Pathology, Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea.
Oncogenesis. 2021 Dec 10;10(12):85. doi: 10.1038/s41389-021-00365-4.
Genomic stability maintenance requires correct DNA replication, chromosome segregation, and DNA repair, while defects of these processes result in tumor development or cell death. Although abnormalities in DNA replication and repair regulation are proposed as underlying causes for genomic instability, the detailed mechanism remains unclear. Here, we investigated whether NKX6.3 plays a role in the maintenance of genomic stability in gastric epithelial cells. NKX6.3 functioned as a transcription factor for CDT1 and RPA1, and its depletion increased replication fork rate, and fork asymmetry. Notably, we showed that abnormal DNA replication by the depletion of NKX6.3 caused DNA damage and induced homologous recombination inhibition. Depletion of NKX6.3 also caused copy number alterations of various genes in the vast chromosomal region. Hence, our findings underscore NKX6.3 might be a crucial factor of DNA replication and repair regulation from genomic instability in gastric epithelial cells.
基因组稳定性的维持需要正确的DNA复制、染色体分离和DNA修复，而这些过程的缺陷会导致肿瘤发生或细胞死亡。尽管DNA复制和修复调控异常被认为是基因组不稳定的潜在原因，但其详细机制仍不清楚。在这里，我们研究了NKX6.3是否在胃上皮细胞基因组稳定性的维持中发挥作用。NKX6.3作为CDT1和RPA1的转录因子发挥作用，其缺失会增加复制叉速率和叉不对称性。值得注意的是，我们发现NKX6.3缺失导致的异常DNA复制会引起DNA损伤并诱导同源重组抑制。NKX6.3的缺失还会导致大片染色体区域中各种基因的拷贝数改变。因此，我们的研究结果强调NKX6.3可能是胃上皮细胞基因组不稳定时DNA复制和修复调控的关键因素。
