Replication stress links structural and numerical cancer chromosomal instability.
Replication stress links structural and numerical cancer chromosomal instability.
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DOI：
10.1038/nature11935
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发表时间：
2013-02-28
期刊：
影响因子：
64.8
通讯作者：
Swanton C
中科院分区：
文献类型：
--
作者：
Burrell RA;McClelland SE;Endesfelder D;Groth P;Weller MC;Shaikh N;Domingo E;Kanu N;Dewhurst SM;Gronroos E;Chew SK;Rowan AJ;Schenk A;Sheffer M;Howell M;Kschischo M;Behrens A;Helleday T;Bartek J;Tomlinson IP;Swanton C
癌症染色体不稳定性（CIN）导致染色体数量和结构的变化率升高，并产生肿瘤内异质性。在大多数实体肿瘤中都观察到CIN，它与不良预后和耐药性相关。因此，了解CIN的机制基础至关重要。在此我们发现，与CIN - 结直肠癌细胞相比，CIN + 结直肠癌细胞存在复制叉进展受阻和DNA复制应激升高的证据，染色体结构异常导致有丝分裂中染色体错误分离。我们确定了位于18号染色体长臂（18q）上编码的三个新的CIN抑制基因（PIGN（MCD4）、RKHD2（MEX3C）和ZNF516（KIAA0222）），在CIN + 结直肠癌中18q经常发生拷贝数丢失。18q丢失在时间上与腺瘤 - 癌转变过程中的非整倍体出现相关。CIN抑制基因沉默导致DNA复制应激、染色体结构异常和染色体错误分离。给细胞补充核苷以减轻复制相关损伤，可降低CIN抑制基因沉默后染色体分离错误的频率，并减少CIN + 细胞中的分离错误和DNA损伤。这些数据表明复制应激在结构性和数量性CIN产生中起核心作用，这可能为限制肿瘤内异质性的新治疗方法提供依据。
Cancer chromosomal instability (CIN) results in an elevated rate of change of chromosome number and structure and generates intratumour heterogeneity. CIN is observed in the majority of solid tumours and is associated with both poor prognosis and drug resistance. Therefore, understanding a mechanistic basis for CIN is paramount. Here we find evidence for impaired replication fork progression and elevated DNA replication stress in CIN+ colorectal cancer (CRC) cells relative to CIN− CRC cells, with structural chromosome abnormalities precipitating chromosome missegregation in mitosis. We identify three novel CIN-suppressor genes (PIGN (MCD4), RKHD2 (MEX3C) and ZNF516 (KIAA0222)) encoded on chromosome 18q, which is subject to frequent copy number loss in CIN+ CRC. 18q loss was temporally associated with aneuploidy onset at the adenoma-carcinoma transition. CIN-suppressor gene silencing leads to DNA replication stress, structural chromosome abnormalities and chromosome missegregation. Supplementing cells with nucleosides, to alleviate replication-associated damage, reduces the frequency of chromosome segregation errors following CIN-suppressor gene silencing and attenuates segregation errors and DNA damage in CIN+ cells. These data implicate a central role for replication stress in the generation of structural and numerical CIN, which may inform new therapeutic approaches to limit intratumour heterogeneity.