Deletion of Brca2 exon 27 causes hypersensitivity to DNA crosslinks, chromosomal instability, and reduced life span in mice
Deletion of Brca2 exon 27 causes hypersensitivity to DNA crosslinks, chromosomal instability, and reduced life span in mice
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DOI：
10.1002/gcc.10148
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发表时间：
2003-04-01
影响因子：
3.7
通讯作者：
Hasty, P
中科院分区：
文献类型：
--
作者：
Donoho, G;Brenneman, MA;Hasty, P
Brca 2肿瘤抑制基因有助于基因组的稳定性，至少部分是通过同源重组修复的作用。推测BRCA 2蛋白通过与RAD 51相互作用在同源重组中起作用。Brca 2的外显子II和27都编码与RAD 51相互作用的结构域;外显子11编码8个BRC基序，而外显子27编码单个不同的相互作用结构域。所有RAD 51相互作用结构域的缺失导致小鼠胚胎死亡。在BRAC 2截短的情况下观察到不太严重的表型，其保留了一些但不是全部的BRC基序。这些小鼠可以在断奶后存活，但发育不良且不能生育，并在很小的时候死于癌症。来自这些小鼠的细胞显示对某些遗传毒性剂的超敏反应和染色体不稳定性。在这里，我们已经分析了小鼠和细胞的RAD 51相互作用区域的外显子27编码的缺失。这种突变（称为brca 2（1 exe 1））的纯合子小鼠的寿命比对照组小鼠短，这可能是因为癌症和败血症的早期发病。在这些动物中未观察到其他表型;因此，brca 2（1 exe 1）突变的严重程度低于删除一些BRC基序的截短。然而，在细胞水平上，brca 2（1 exe 1）突变导致活力降低，对DNA链间交联剂丝裂霉素C的超敏反应，以及总的染色体不稳定性，就像更严重的截短一样。因此，由外显子27编码的极端羧基末端区域对于BRCA 2功能是重要的，可能是因为它是BRCA 2和RAD 51之间的全功能相互作用所必需的。(C)2003 Wiley-Liss，Inc.
The Brca2 tumor-suppressor gene contributes to genomic stability, at least in part by a role in homologous recombinational repair. BRCA2 protein is presumed to function in homologous recombination through interactions with RAD51. Both exons I I and 27 of Brca2 code for domains that interact with RAD51; exon 11 encodes eight BRC motifs, whereas exon 27 encodes a single, distinct interaction domain. Deletion of all RAD51-interacting domains causes embryonic lethality in mice. A less severe phenotype is seen with BRAC2 truncations that preserve some, but not all, of the BRC motifs. These mice can survive beyond weaning, but are runted and infertile, and die very young from cancer. Cells from such mice show hypersensitivity to some genotoxic agents and chromosomal instability. Here, we have analyzed mice and cells with a deletion of only the RAD51-interacting region encoded by exon 27. Mice homozygous for this mutation (called brca2(1exe1)) have a shorter life span than that of control littermates, possibly because of early onsets of cancer and sepsis. No other phenotype was observed in these animals; therefore, the brca2(1exe1) mutation is less severe than truncations that delete some BRC motifs. However, at the cellular level, the brca2(1exe1) mutation causes reduced viability, hypersensitivity to the DNA interstrand crosslinking agent mitomycin C, and gross chromosomal instability, much like more severe truncations. Thus, the extreme carboxy-terminal region encoded by exon 27 is important for BRCA2 function, probably because it is required for a fully functional interaction between BRCA2 and RAD51. (C) 2003 Wiley-Liss, Inc.