Rare germ line CHEK2 variants identified in breast cancer families encode proteins that show impaired activation.
Rare germ line CHEK2 variants identified in breast cancer families encode proteins that show impaired activation.
复制标题
在乳腺癌家族中发现的罕见种系 CHEK2 变异编码的蛋白质显示出激活受损。
作者：
N. Sodha;T. Mantoni;S. Tavtigian;R. Eeles;M. Garrett
已发现CHEK 2（编码响应于DNA损伤而激活的Chk 2丝氨酸/苏氨酸激酶的基因）中的种系突变赋予某些癌症的增加的风险。我们以前报道了遗传性乳腺癌中常见的有害1100 delC和四种罕见的CHEK 2突变的存在。在这里，我们报告说，生物信息学分析对罕见突变的预测表明，其中两个，delE 161（483- 485 delAGA）和R117 G，可能是有害的。我们发现，由1100 delC和delE 161编码的蛋白质都是不稳定的，并且在Thr 68处响应于DNA损伤而磷酸化效率低下，这是Chk 2寡聚化所必需的步骤。寡聚化反过来又是蛋白质的额外磷酸化和完全活化所必需的。第二个罕见突变R117 G在Thr 68处被磷酸化，但未能显示DNA损伤的迁移率变化，这表明它未能进一步磷酸化，因此完全激活。我们的研究结果表明，delE 161和R117 G编码非功能性蛋白，因此可能是致病性的。生化分析的结果与生物信息学分析的预测有很好的相关性。此外，这些结果意味着这些突变以及1100 delC不能以显性负性方式引起癌症，与这些突变相关的肿瘤发生可能是由于单倍不足。
Germ line mutations in CHEK2, the gene that encodes the Chk2 serine/threonine kinase activated in response to DNA damage, have been found to confer an increased risk of some cancers. We have previously reported the presence of the common deleterious 1100delC and four rare CHEK2 mutations in inherited breast cancer. Here, we report that predictions made by bioinformatic analysis on the rare mutations indicate that two of these, delE161 (483-485delAGA) and R117G, are likely to be deleterious. We show that the proteins encoded by 1100delC and delE161 are both unstable and inefficiently phosphorylated at Thr68 in response to DNA damage, a step necessary for the oligomerization of Chk2. Oligomerization is in turn necessary for additional phosphorylation and full activation of the protein. A second rare mutation, R117G, is phosphorylated at Thr68 but fails to show a mobility shift on DNA damage, suggesting that it fails to become further phosphorylated and hence fully activated. Our results indicate that delE161 and R117G encode nonfunctional proteins and are therefore likely to be pathogenic. The findings from the biochemical analysis correlate well with predictions made by bioinformatics analysis. In addition, the results imply that these mutations, as well as 1100delC, cannot act in a dominant-negative manner to cause cancer, and tumorigenesis in association with these mutations may be due to haploinsufficiency.
影响因子：
11.2
作者：
Sean-Bong Lee;S. H. Kim;D. Bell;D. Wahrer;T. Schiripo;Melissa M. Jorczak;D. Sgroi;J. Garber
通讯作者：
Sean-Bong Lee;S. H. Kim;D. Bell;D. Wahrer;T. Schiripo;Melissa M. Jorczak;D. Sgroi;J. Garber
影响因子：
9.8
作者：
Dong, XY;Wang, L;Liu, WG
通讯作者：
Liu, WG