Detection of a tandem BRCT in Nbs1 and Xrs2 with functional implications in the DNA damage response
Detection of a tandem BRCT in Nbs1 and Xrs2 with functional implications in the DNA damage response
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DOI：
10.1093/bioinformatics/btl075
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发表时间：
2006-06-01
期刊：
影响因子：
5.8
通讯作者：
Guerois, Raphael
中科院分区：
文献类型：
--
作者：
Becker, Emmanuelle;Meyer, Vincent;Guerois, Raphael
动机：人Nbs 1及其在酿酒酵母中的同源物Xrs 2是保守的MRN复合物（酵母中的MRX）的一部分，其在维持基因组稳定性中起关键作用。NBS 1对应于被称为辐射超敏感性疾病的奈梅亨断裂综合征（NBS）中突变的基因。尽管保守和MRN复杂的重要性，高序列之间的分歧Nbs 1和Xrs 2排除了识别的N-末端叉头相关（FHA）domain.Results下游的共同域：使用HMM-HMM配置文件比较和结构建模，我们评估了存在的串联BRCT在Nbs 1和Xrs 2后的FHA。Nbs 1串联BRCT的基于结构的保守性分析支持其作为磷酸丝氨酸结合结构域的功能。值得注意的是，在95%的NBS患者中观察到的5 bp缺失在接头区切割串联体，同时在所得截短的基因产物中保留每个BRCT结构域的结构完整性。
Motivation: Human Nbs1 and its homolog Xrs2 in Saccharomyces cerevisiae are part of the conserved MRN complex (MRX in yeast) which plays a crucial role in maintaining genomic stability. NBS1 corresponds to the gene mutated in the Nijmegen breakage syndrome (NBS) known as a radiation hyper-sensitive disease. Despite the conservation and the importance of the MRN complex, the high sequence divergence between Nbs1 and Xrs2 precluded the identification of common domains downstream of the N-terminal Fork-Head Associated (FHA) domain.Results: Using HMM-HMM profile comparisons and structure modelling, we assessed the existence of a tandem BRCT in both Nbs1 and Xrs2 after the FHA. The structure-based conservation analysis of the tandem BRCT in Nbs1 supports its function as a phosphoserine binding domain. Remarkably, the 5 bp deletion observed in 95% of NBS patients cleaves the tandem at the linker region while preserving the structural integrity of each BRCT domain in the resulting truncated gene products.