Causal link between microsatellite instability and hMRE11 dysfunction in human cancers.
Causal link between microsatellite instability and hMRE11 dysfunction in human cancers.
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DOI：
10.1158/1541-7786.mcr-11-0322
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Her C
中科院分区：
文献类型：
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作者：
Wu X;Xu Y;Chai W;Her C
基因组完整性的维持对于细胞存活是必不可少的，并且基因组不稳定性是所有癌症的公认固有特性。微卫星不稳定性（MSI）是一种常见的、易于追踪的简单序列变异形式，其特征是含有短串联重复序列的特定DNA序列的收缩或扩张。MSI经常在具有DNA错配修复（MMR）缺陷的肿瘤细胞中检测到。通常认为，在单个微卫星位点的不稳定性可以自发地在细胞中独立于MMR状态而出现，并且不同的微卫星位点通常不均匀地受到MMR缺陷的影响。众所周知，MMR缺陷本身不足以引发肿瘤发生;相反，生物学效应必须通过控制细胞存活、DNA损伤反应和细胞凋亡的基因突变来发挥。最近，内含子hMRE 11聚（T）11道的缩短与MMR缺陷有关，这增加了hMRE 11可能被缺陷的MMR灭活的可能性。然而，这种关联背后的分子本质目前尚不清楚，对当前文献的回顾表明，hMRE 11最有可能以更复杂的方式参与MMR通路，而不仅仅是MMR靶基因。提出了一种替代方案，以更好地协调各种研究之间的差异。hMRE 11在端粒重复序列稳定性中的潜在作用也进行了讨论。
Maintenance of genomic integrity is essential for cell survival, and genomic instability is a commonly recognized intrinsic property of all cancers. Microsatellite instability (MSI) represents a frequently occurring and easily traceable simple form of sequence variation signified by the contraction or expansion of specific DNA sequences containing short tandem repeats. MSI is frequently detected in tumor cells with DNA mismatch repair (MMR) deficiency. It is commonly conceived that instability at individual microsatellite loci can arise spontaneously in cells independent of MMR status, and different microsatellite loci are generally not affected uniformly by MMR deficiency. It is well recognized that MMR deficiency per se is not sufficient to initiate tumorigenesis; rather the biological effects have to be exerted by mutations in genes controlling cell survival, DNA damage response, and apoptosis. Recently, shortening of an intronic hMRE11 poly(T)11 tract has been associated with MMR deficiency, raising the possibility that hMRE11 may be inactivated by defective MMR. However, the molecular nature underlying this association is presently unknown, and review of the current literature suggests that hMRE11 is most likely involved with the MMR pathway in a more complex fashion than just being a MMR target gene. An alternative scenario is proposed to better reconcile the differences among various studies. The potential role of hMRE11 in telomere repeats stability is also discussed.