RESUMEN
Two recent papers provide new evidence relevant to the role of the breast cancer susceptibility gene BRCA2 in DNA repair. Moynahan et al provide genetic data indicating a requirement for BRCA2 in homology-dependent (recombinational) repair of DNA double-strand breaks. The second paper, by Davies et al, begins to address the mechanism through which BRCA2 makes its contribution to recombinational repair. BRCA2 appears to function in recombination via interactions with the major eukaryotic recombinase RAD51 [1,2,3]. We briefly review the context in which the two studies were carried out, we comment on the results presented, and we discuss models designed to account for the role of BRCA2 in RAD51-mediated repair.
Asunto(s)
Neoplasias de la Mama/genética , Proteínas de Neoplasias/genética , Factores de Transcripción/genética , Proteína BRCA2 , Reparación del ADN , Proteínas de Unión al ADN/genética , Femenino , Humanos , Recombinasa Rad51 , Recombinación GenéticaRESUMEN
The breast cancer susceptibility gene BRCA1 encodes a multifunctional protein that is mutated in many hereditary breast and ovarian cancers. We have cloned a homologue of the human BRCA1 gene from chicken; the gene encodes a 1749 amino acid protein that is 33% identical to human BRCA1. Phylogenetic analyses of the chicken and mammalian proteins indicate that the chicken gene is a bona fide BRCA1 orthologue, the first to be described from a non-mammal. Most of the chicken protein has diverged considerably from its mammalian orthologues, although the RING and BRCT repeat regions are highly conserved. This marked overall sequence divergence has allowed us to identify nine additional highly-conserved motifs (ranging from 8--56 amino acids in length) which are likely important for BRCA1 function.
Asunto(s)
Proteína BRCA1/química , Proteína BRCA1/genética , Pollos/genética , Genes BRCA1 , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Proteínas Aviares , Embrión de Pollo , Clonación Molecular , Secuencia Conservada , Humanos , Datos de Secuencia Molecular , Filogenia , Homología de Secuencia de AminoácidoRESUMEN
Loss of a whole chromosome 5, or a del(5q), is a recurring abnormality in malignant myeloid diseases. By cytogenetic and molecular analyses, we delineated previously a 1- to 1.5-Mb region that is deleted in all patients with a del(5q). In our efforts to identify a myeloid tumor suppressor gene within the commonly deleted segment (CDS), we have cloned and characterized the genes encoding three putative nuclear proteins, each of which contains a bipartite nuclear localization signal (NLS). In addition, C5ORF5 contains a putative rhoGAP domain at the N-terminus, C5ORF6 has a proline-rich sequence near the N-terminus, and C5ORF7 has a zinc-finger domain that partially overlaps the NLS. All three genes are ubiquitously expressed and encode novel proteins. The C5ORF5 cDNA is 5.47 kb encoding a protein of 915 amino acids (aa) with a predicted molecular mass of approximately 105 kDa. C5ORF5 has 23 exons spanning over 27 kb. The C5ORF6 transcript is 4.1 kb encoding a protein of 392 aa with a predicted molecular mass of approximately 43 kDa. C5ORF6 has 5 exons and spans approximately 11 kb. The C5ORF7 cDNA is 6.3 kb and encodes a protein of 1417 aa with a predicted molecular mass of approximately 155 kDa. C5ORF7 has 24 exons spanning approximately 64 kb. All three genes were localized to the distal half of the CDS between D5S1983 and D5S500. We evaluated each as a candidate tumor suppressor gene by the analysis of myeloid leukemia cells from patients with -5/del(5q), but no inactivating mutations were identified.
Asunto(s)
Cromosomas Humanos Par 5 , Genes Supresores de Tumor , Leucemia Mieloide/genética , Síndromes Mielodisplásicos/genética , Proteínas Nucleares/genética , Secuencia de Aminoácidos , Mapeo Cromosómico , Humanos , Datos de Secuencia Molecular , Señales de Localización Nuclear , Polimorfismo Conformacional Retorcido-Simple , Homología de Secuencia de AminoácidoRESUMEN
The Drosophila kelch protein is a structural component of ring canals and is required for oocyte maturation. Here, we report the cloning and genomic structure of a new human homologue of kelch, KLHL3. At the amino acid level, KLHL3 shares 77% similarity with Drosophila kelch and 89% similarity with Mayven (KLHL2), another human kelch homolog. The approximately 6.5-kb mRNA has a single open reading frame encoding a protein of 587 amino acids with a predicted molecular mass of 650 kDa. Like kelch and KLHL2, the KLHL3 protein contains a poxvirus and zinc finger domain at the N-terminus and six tandem repeats (kelch repeats) at the C-terminus. At least three isoforms, which differ in the length of the N-terminus, are produced and may be the result of alternative promoter usage. We also identified alternative polyadenylation sites and alternative splicing; thus, as many as 12 mRNA variants and six putative protein isoforms could be produced. The KLHL3 gene is mapped to human chromosome 5, band q31, contains 17 exons, and spans approximately 120 kb of genomic DNA. KLHL3 maps within the smallest commonly deleted segment in myeloid leukemias characterized by a deletion of 5q; however, we detected no inactivating mutations of KLHL3 in malignant myeloid disorders with loss of 5q.