The BRCA1 C-terminal domain: structure and function

Huyton, Trevor; Bates, Paul A.; Zhang, Xiaodong; Sternberg, Michael J.E.; Freemont, Paul S.

doi:10.1016/s0921-8777(00)00034-3

Cited by 141 publications

(123 citation statements)

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“…The structures of BRCT containing proteins have revealed that the conserved set of BRCT residues, which contribute to the hydrophobic core and overall fold of these domains, are found within the central β-sheet, in helix α3, and at the C-terminus of helix α1 8,10-12 . In general, there are few invariant residues amongst the BRCTs, and the sequences diverge greatly in regions that form the BRCT α2, and in two hypervariable insertion regions that are found at the β1-α1 and β2-β3 junctions 6,7,9 . These variable regions were originally hypothesized to form adaptable protein-protein interaction surfaces 8 .…”

Section: Discussionmentioning

confidence: 99%

“…BRCT repeats are found not only in BRCA1, but in a large number of other proteins that respond to DNA damage [5][6][7] . A number of structural studies have revealed a conserved structure for the repeat, consisting of a 4-stranded parallel β sheet flanked by a pair of α helices on one face (α1 and α3), and a single α helix (α2) on the opposite face [8][9][10][11][12][13] . The two BRCT repeats of BRCA1 pack in a head-to-tail manner involving α2 of the N-terminal repeat and α1 and α3 of the Cterminal repeat, as well as inter-repeat linker 10,11 .…”

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confidence: 99%

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Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1

Williams

Lee

Hau

et al. 2004

Nat Struct Mol Biol

221

288

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1

Williams

Lee

Hau

et al. 2004

Nat Struct Mol Biol

221

288

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“…1C) and has been proposed to be responsible for determining functional specificity of the BRCT domains. 26 Interestingly, Lund 279 presents almost exclusively ovarian cancer cases and no breast cancer cases raising the possibility of differential effects of this mutant in breast versus ovary epithelia. That observation led us to test the temperature-sensitiveness in breast cancer and ovarian cancer cell lines.…”

Section: Discussionmentioning

confidence: 99%

A Naturally Occurring Allele of BRCA1 Coding for a Temperature-Sensitive Mutant Protein

Worley¹,

Vallon‐Christersson²,

Billack³

et al. 2002

Cancer Biology & Therapy

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© 2 0 0 2 L a n d e s B i o s c i e n c e . N o t f o r d i s t r i b u t i o n .[Cancer Biology & Research PaperA Naturally Occurring Allele of BRCA1 Coding for a TemperatureSensitive Mutant Protein ABSTRACT Recent evidence suggests that the breast and ovarian cancer susceptibility gene product BRCA1 is involved in at least two fundamental cellular processes: transcriptional regulation and DNA repair. However, the mechanism of action of BRCA1 in either of these processes is still unknown. Here, we report the characterization of a disease-predisposing allele of BRCA1, identified in a family with several cases of ovarian cancer, coding for a protein that displays temperature-sensitive activity in transcriptional activation. The mutant protein differs from the wild type protein at a single amino acid, R1699W that occurs in a region at the N-terminal BRCT domain that is highly conserved among BRCA1 homologs. When the C-terminus of the mutant protein (aa 1560-1863) was fused to a heterologous GAL4 DNA-binding domain and expressed in yeast or mammalian cells, it was able to activate transcription of a reporter gene to levels observed for wild type BRCA1 at the permissive temperature (30˚C) but exhibited significantly less transcription activity at the restrictive temperature (37˚C or 39˚C). Our results indicate that the transcriptional activity of the R1699W mutant can be modulated as a function of temperature and provide a novel experimental approach which can be utilized to dissect the molecular mechanism(s) of BRCA1 in processes related to transcription.

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“…BRCA1 contains two known functional domains located in the N-and C-terminal regions which are highly conserved: one RING finger domain (24-64 aa), two BRCT domains (BRCA1 C-terminus) (1649-1736, 1756-1855 aa) (Koonin et al, 1996). BRCT domains are present in many proteins involved in DNA repair, but their biological functions are still unclear (Huyton et al, 2000). BRCA1 interacts directly or indirectly with numerous proteins involved in various cellular pathways: transcriptional regulation, cell cycle/checkpoint control, protein ubiquitination, chromatin remodelling, and DNA repair (see Venkitaraman (2002) for review).…”

Section: Introductionmentioning

confidence: 99%

Fidelity of DNA double-strand break repair in heterozygous cell lines harbouring BRCA1 missense mutations

et al. 2003

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Germ-line mutations of the BRCA1 and BRCA2 genes, when they lead to a truncated protein, confer a high risk of breast and ovarian cancer. However, the role of BRCA1 missense mutations in cancer predisposition is unclear. Functional assays may be very helpful to more clearly define the biological effect of these mutations, and could therefore be useful in clinical practice. A recent study using a Host Cell End-Joining assay showed that a truncating mutation results in impaired fidelity of DSB repair by DNA end-joining. In the present study, we examined the fidelity of DSB repair in four lymphoblastoid cell lines with BRCA1 missense mutations. The fidelity of DNA end-joining was impaired in the four cell lines studied compared to the normal control cell line. The fidelity of end-joining was similar to that of a truncated mutation control cell line for one cell line and slightly higher for the other cell lines.

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The BRCA1 C-terminal domain: structure and function

Cited by 141 publications

References 50 publications

Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1

Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1

A Naturally Occurring Allele of BRCA1 Coding for a Temperature-Sensitive Mutant Protein

Fidelity of DNA double-strand break repair in heterozygous cell lines harbouring BRCA1 missense mutations

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