MBD4 deficiency does not increase mutation or accelerate tumorigenesis in mice lacking MMR
MBD4 deficiency does not increase mutation or accelerate tumorigenesis in mice lacking MMR
复制标题
DOI：
10.1038/sj.onc.1207767
复制
发表时间：
2004-07-22
期刊：
影响因子：
8
通讯作者：
Clarke, AR
中科院分区：
文献类型：
--
作者：
Sansom, OJ;Bishop, SM;Clarke, AR
Mbd4（甲基结合域 4）已被证明在错配修复 (MMR) 缺陷的结直肠肿瘤中发生突变，且表现出微卫星不稳定性 (MSI)。然而，这些突变的意义仍不清楚，因为它们主要是单等位基因，并且大多数发生在多聚 A 区域。除了 MMR 缺陷型肿瘤外，尚未发表有关人类肿瘤中 Mbd4 突变的其他报道。为了解决在没有 MMR 的情况下 Mbd4 缺失的重要性，我们将 Mbd4 缺陷型小鼠与缺乏 DNA MMR 的小鼠进行了杂交。我们发现，在 MMR 缺陷的情况下，与单突变 Msh2 或 Mlh1 小鼠相比，Mbd4 的额外缺失不会改变内源 DIb-1b 位点的自发突变频率，也不会改变肿瘤发生、肿瘤谱或 MSI。总而言之，这些发现表明 Mbd4 的无效性或杂合性不会影响 MMR 依赖性肿瘤发生。
Mbd4 (methyl-binding domain 4) has been shown to be mutated in a high percentage of mismatch repair (MMR)deficient colorectal tumours that exhibit microsatellite instability (MSI). However, the significance of these mutations is still unclear as they are predominantly monoallelic and the majority occur at a poly-A tract. Apart from MMR-deficient tumours, no other reports of mutations of Mbd4 in human neoplasia are as yet published. To address the significance of loss of Mbd4 in the absence of MMR, we have crossed Mbd4-deficient mice to mice lacking DNA MMR. We show that, in the context of MMR deficiency, additional loss of Mbd4 does not alter spontaneous mutation frequency at the endogenous DIb-1b locus, nor does it modify tumour onset, tumour spectrum or MSI compared to singly mutant Msh2 or Mlh1 mice. Taken together, these findings show that nullizygosity or heterozygosity for Mbd4 does not affect MMR-dependent tumorigenesis.