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BRCA1 haploinsufficiency for replication stress suppression in primary cells
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BRCA1 haploinsufficiency for replication stress suppression in primary cells
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Journal Article
BRCA1 haploinsufficiency for replication stress suppression in primary cells
2014
Overview
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
BRCA1
mut/+
mammary epithelial cells and fibroblasts. Here we report that all
BRCA1
mut/+
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
BRCA1
mut/+
cells with wt BRCA1. In addition, we observed ‘conditional’ haploinsufficiency for HR-DSBR in
BRCA1
mut/+
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
Subject
/ 13/106
/ 14
/ 14/1
/ 64
/ 64/60
/ Animals
/ DNA Replication - physiology
/ Female
/ Haploinsufficiency - genetics
/ Haploinsufficiency - physiology
/ Humanities and Social Sciences
/ Humans
/ Mice
/ Rad51 Recombinase - genetics
/ Rad51 Recombinase - physiology
/ Recombinational DNA Repair - genetics
/ Recombinational DNA Repair - physiology
/ Science
