Insights into the functions of BRCA1 and BRCA2

doi:10.1016/S0168-9525(99)01930-7

Trends in Genetics

Volume 16, Issue 2, 1 February 2000, Pages 69-74

https://doi.org/10.1016/S0168-9525(99)01930-7 Get rights and content

Abstract

Since BRCA1 and BRCA2 were cloned five years ago, unraveling their normal functions has posed fascinating problems for cancer biologists. Both genes are novel, and little of their normal function was revealed by their sequence. Both genes contribute to homologous recombination and DNA repair, to embryonic proliferation, to transcriptional regulation and, for BRCA1, to ubiquitination. But questions regarding BRCA1 and BRCA2 biology remain, and their resolution is critical for clinical development. Why do ubiquitously expressed genes that participate in universal pathways lead, when mutant, specifically to breast and ovarian cancer? Why are the same genes required for embryonic proliferation and for tumor suppression?

Section snippets

Structural clues to biological function

Although the breast and ovarian cancer phenotypes associated with mutation in BRCA1 and BRCA2 are similar, the genes are not detectably related by sequence. Given their differences in primary sequence, the genomic parallels between the two genes are particularly striking: both genes are large and span approximately 80 kb of genomic DNA; both have extremely large central exons encoding >50% of the protein; and both genes encode large proteins, 1 863 and 3 418 amino acids, respectively.

Cellular expression of BRCA1 and BRCA2

In normal cells, BRCA1 and BRCA2 are nuclear proteins19, 30. BRCA1 protein expression is reduced or absent in most sporadic, advanced (grade III) ductal breast carcinomas³¹. (The suggestion that BRCA1 was secreted³² was based on use of a BRCA1 antibody that cross-reacts with membrane-bound extracellular growth factor, and hence was erroneous.) Nuclear localization signals have been identified for BRCA1 (Ref. 33) and BRCA2 (Ref. 34). BRCA1 nuclear localization domains interact with importin-α, a

Expression of BRCA1 and BRCA2 in development

BRCA1 and BRCA2 are expressed ubiquitously with highest levels in the thymus and testis². In developing mouse embryos, both genes are most highly expressed in rapidly dividing, differentiating tissues and, most notably, during mammary epithelial proliferation and differentiation17, 43. In the mammary gland, the expression of both messages is developmentally regulated and is induced during puberty and pregnancy and reduced during lactation⁴³. The spatial and temporal patterns of Brca1 and Brca2

Role of BRCA1 and BRCA2 in DNA repair

A role for BRCA1 and BRCA2 in homologous recombination and DNA repair is suggested by the strong biochemical interaction of BRCA1 and BRCA2 with proteins known to be involved in these processes. The involvement of BRCA1 and BRCA2 in complexes that activate double-strand break repair and initiate homologous recombination links the maintenance of genomic integrity to tumor suppression. BRCA2 and RAD51 interact and co-localize in a BRCA1– BRCA2–RAD51 complex6, 7. Eukaryotic RAD51 proteins are

Roles of BRCA1 and BRCA2 in transcriptional regulation

The possibility that BRCA1 is a transcriptional regulator is suggested both by the interactions of BRCA1 with RNA helicase A and with CtIP as part of the transcriptional complex19, 50, 57 (Fig. 4) and by the behavior of BRCA1 in transcriptional activation assays20, 21. Clinically relevant mutations at the 3′ end of BRCA1 reduce the BRCA1–RNA helicase A association. The BRCA1 C-terminus (amino acids 1528–1863) induces transcription from reporter plasmids in mammalian and yeast cells when fused

Future directions

How does loss of BRCA1 or BRCA2 function lead to breast or ovarian cancer? Furthermore, why do genes that are ubiquitously expressed and participate in universal cellular pathways lead, when mutant, specifically (or almost specifically) to breast and ovarian cancer?

It is clear from the genetics of human families that normal BRCA1 and BRCA2 suppress tumorigenesis. However, there is not yet experimental proof that BRCA1 and BRCA2 are tumor suppressors, in the sense that RB was proven to be a

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Trends in Genetics

ReviewInsights into the functions of BRCA1 and BRCA2

Abstract

Section snippets

Structural clues to biological function

Cellular expression of BRCA1 and BRCA2

Expression of BRCA1 and BRCA2 in development

Role of BRCA1 and BRCA2 in DNA repair

Roles of BRCA1 and BRCA2 in transcriptional regulation

Future directions

Cell

Mol. Cell

Mol. Cell

Cell

Dev. Biol.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Mol. Cell

Cell

Cell

J. Biol. Chem.

Cell

Linkage of early-onset familial breast cancer to chromosome 17q21

Science

A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1

Science

Identification of the breast cancer susceptibility gene BRCA2

Nature

Allele losses in the region 17q12–21 in familial breast and ovarian cancer involve the wild-type chromosome

Nat. Genet.

The genetics of breast cancer susceptibility

Annu. Rev. Genet.

BRCA1 required for transcription-coupled repair of oxidative DNA damage

Science

Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities

Nat. Genet.

Inactivation of the mouse Brca1 gene leads to failure in the morphogenesis of the egg cylinder in early postimplantation development

Genes Dev.

Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2

Nature

Brca2 is required for embryonic cellular proliferation in the mouse

Genes Dev.

Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos

Genes Dev.

Tumorigenesis and a DNA-repair defect in mice with a truncating Brca2 mutation

Nat. Genet.

RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination

Proc. Natl. Acad. Sci. U. S. A.

BRCA1 is a component of the RNA polymerase II holoenzyme

Proc. Natl. Acad. Sci. U. S. A.

Transcriptional activation by BRCA1

Nature

Evidence for a transcriptional activation function of BRCA1 C-terminal region

Proc. Natl. Acad. Sci. U. S. A.

Transcriptional activation functions in BRCA2

Nature

Review
Insights into the functions of BRCA1 and BRCA2