BRCA1 haploinsufficiency for replication stress suppression in primary cells.
BRCA1 haploinsufficiency for replication stress suppression in primary cells.
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DOI：
10.1038/ncomms6496
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发表时间：
2014-11-17
影响因子：
16.6
通讯作者：
Livingston, David M.
中科院分区：
文献类型：
--
作者：
Pathania, Shailja;Bade, Sangeeta;Le Guillou, Morwenna;Burke, Karly;Reed, Rachel;Bowman-Colin, Christian;Su, Ying;Ting, David T.;Polyak, Kornelia;Richardson, Andrea L.;Feunteun, Jean;Garber, Judy E.;Livingston, David M.
BRCA1是一种乳腺和卵巢癌抑制基因，可促进基因组完整性。为了研究杂合状态下BRCA1的功能，我们建立了原代人BRCA1+/+和BRCA1mut/+乳腺上皮细胞和成纤维细胞集合。在此我们报道，所有BRCA1mut/+细胞都表现出多种正常的BRCA1功能，包括对同源重组型双链断裂修复（HR - DSBR）的支持、检查点功能、中心体数量控制、纺锤极形成、Slug表达以及卫星RNA抑制。相比之下，这些相同的细胞在停滞的复制叉修复和/或抑制复制叉崩溃（即复制应激）方面存在缺陷。通过用野生型BRCA1重建BRCA1mut/+细胞，这些缺陷得以修复。此外，我们观察到在面临复制应激时，BRCA1mut/+细胞中存在HR - DSBR的“条件性”单倍体不足。鉴于复制应激在上皮癌发展中的重要性以及HR缺陷在乳腺癌发病机制中的重要性，这两种缺陷都可能是BRCA1缺陷乳腺组织中肿瘤发生的促成因素。
BRCA1是参与双链断裂修复的关键乳腺和卵巢癌抑制因子。在此，作者表明，几种BRCA1突变的杂合细胞在对复制应激的反应中普遍存在缺陷，这可能有助于BRCA1乳腺癌发展途径。
BRCA1—a breast and ovarian cancer suppressor gene—promotes genome integrity. To study the functionality of BRCA1 in the heterozygous state, we established a collection of primary human BRCA1+/+ and BRCA1mut/+ mammary epithelial cells and fibroblasts. Here we report that all BRCA1mut/+ cells exhibited multiple normal BRCA1 functions, including the support of homologous recombination- type double-strand break repair (HR-DSBR), checkpoint functions, centrosome number control, spindle pole formation, Slug expression and satellite RNA suppression. In contrast, the same cells were defective in stalled replication fork repair and/or suppression of fork collapse, that is, replication stress. These defects were rescued by reconstituting BRCA1mut/+ cells with wt BRCA1. In addition, we observed ‘conditional’ haploinsufficiency for HR-DSBR in BRCA1mut/+ cells in the face of replication stress. Given the importance of replication stress in epithelial cancer development and of an HR defect in breast cancer pathogenesis, both defects are candidate contributors to tumorigenesis in BRCA1-deficient mammary tissue. BRCA1 is a key breast and ovarian cancer suppressor involved in DSB repair. Here, the authors show that cells heterozygous for several BRCA1 mutations are universally defective in the response to replication stress, which could contribute to the BRCA1 breast cancer development pathway.
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影响因子：
6.4
作者：
Buchholz, TA;Wu, XF;Brock, WA
通讯作者：
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通讯作者：
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作者：
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通讯作者：
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