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BRCA1 and human centromere markers in interphase fibroblasts. (A) BRCA1 (red) and CENP-C (green) in TIG1 cells. (B) BRCA1 (green) and centromeric DNA (red) in IMR90. (C) BRCA1 (green) and CENP-B (red) in TIG1. Asterisks mark sites of association highlighted in insets and arrowheads mark some of the other sites of association.
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fig3: BRCA1 and human centromere markers in interphase fibroblasts. (A) BRCA1 (red) and CENP-C (green) in TIG1 cells. (B) BRCA1 (green) and centromeric DNA (red) in IMR90. (C) BRCA1 (green) and CENP-B (red) in TIG1. Asterisks mark sites of association highlighted in insets and arrowheads mark some of the other sites of association.

Mentions: The aforementioned findings led us to investigate whether BRCA1 has a relationship to heterochromatin associated with centromeres. Using an antibody to centromere protein C (CENP-C), which is a constitutive component of the interphase centromere–kinetochore complex, the patterns of CENP-C and BRCA1 in human fibroblasts (TIG1) were again distinct, yet exhibited a substantial spatial association (Fig. 3 A). We categorized these associations into three types, as follows: 3% of BRCA1 spots were completely coincident with CENP-C spots, another 12% directly abutted or contacted (no separation visible by light microscopy), and an additional 24% were suggestive of a close pairing. Very similar observations (3% coincident, 14% abutting/adjacent, and 16% close) were made when we hybridized to α-satellite DNA (Fig. 3 B) or used CENP-B, which binds α-satellite, as a marker (Fig. 3 C).

BRCA1 foci in normal S-phase nuclei are linked to interphase centromeres and replication of pericentric heterochromatin

Pageau GJ, Lawrence JB - J. Cell Biol. (2006)

Bottom Line: Although BRCA1 does not overlap XIST RNA across the inactive X chromosome, BRCA1 foci position overwhelmingly in heterochromatic regions, particularly the nucleolar periphery where many centromeres reside.BRCA1 loss is often associated with proliferative defects, including postmitotic bridges enriched with satellite DNA.These findings implicate BRCA1 in replication-linked maintenance of centric/pericentric heterochromatin and suggest a novel means whereby BRCA1 loss may contribute to genomic instability and cancer.

Affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.

ABSTRACT
Breast cancer-associated protein 1 (BRCA1) forms foci at sites of induced DNA damage, but any significance of these normal S-phase foci is unknown. BRCA1 distribution does not simply mirror or overlap that of replicating DNA; however, BRCA1 foci frequently abut sites of BrdU incorporation, mostly at mid-to-late S phase. Although BRCA1 does not overlap XIST RNA across the inactive X chromosome, BRCA1 foci position overwhelmingly in heterochromatic regions, particularly the nucleolar periphery where many centromeres reside. In humans and mice, including early embryonic cells, BRCA1 commonly associates with interphase centromere-kinetochore complexes, including pericentric heterochromatin. Proliferating cell nuclear antigen or BrdU labeling demonstrates that BRCA1 localizes adjacent to, or "paints," major satellite blocks as chromocenters replicate, where topoisomerase is also enriched. BRCA1 loss is often associated with proliferative defects, including postmitotic bridges enriched with satellite DNA. These findings implicate BRCA1 in replication-linked maintenance of centric/pericentric heterochromatin and suggest a novel means whereby BRCA1 loss may contribute to genomic instability and cancer.

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