BRCA2: safeguarding the genome through homologous recombination

Christ, Nicole; Moynahan, Mary Ellen; Jasin, Maria

doi:10.1007/4735_2007_0216

Cited by 3 publications

(2 citation statements)

References 88 publications

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“…HR genes have been found to suppress spontaneous and DSB‐induced chromosomal rearrangements in S. cerevisiae , (Myung et al , 2001; Myung and Kolodner, 2003; Deem et al , 2008) and S. pombe (Nakamura et al , 2008). Similarly, the role of HR genes, in particular, BRCA2 , in suppressing chromosomal rearrangements and tumourigenesis in mammalian cells is well established (Christ et al , 2007). Thus, extensive end processing resulting from failed gene conversion may be a general mechanism driving chromosomal rearrangements.…”

Section: Discussionmentioning

confidence: 99%

Failed gene conversion leads to extensive end processing and chromosomal rearrangements in fission yeast

Tinline-Purvis

Savory

Cullen

et al. 2009

EMBO J

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Loss of heterozygosity (LOH), a causal event in cancer and human genetic diseases, frequently encompasses multiple genetic loci and whole chromosome arms. However, the mechanisms by which such extensive LOH arises, and how it is suppressed in normal cells is poorly understood. We have developed a genetic system to investigate the mechanisms of DNA double-strand break (DSB)-induced extensive LOH, and its suppression, using a non-essential minichromosome, Ch 16 , in fission yeast. We find extensive LOH to arise from a new break-induced mechanism of isochromosome formation. Our data support a model in which Rqh1 and Exo1-dependent end processing from an unrepaired DSB leads to removal of the broken chromosome arm and to break-induced replication of the intact arm from the centromere, a considerable distance from the initial lesion. This process also promotes genomewide copy number variation. A genetic screen revealed Rhp51, Rhp55, Rhp57 and the MRN complex to suppress both isochromosome formation and chromosome loss, in accordance with these events resulting from extensive end processing associated with failed homologous recombination repair.

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Section: Discussionmentioning

confidence: 99%

Failed gene conversion leads to extensive end processing and chromosomal rearrangements in fission yeast

Tinline-Purvis

Savory

Cullen

et al. 2009

EMBO J

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“…Given the complex domain structure of BRCA2 and the diverse domain compositions of BRCA2 orthologs in other organisms [27] , we sought to comprehensively investigate the role of BRCA2 domains in HR. We find that mutations that disrupt DNA binding in the DBD significantly reduce or abolish HR when PALB2 binding is absent, while deletion of the entire DBD has little impact on HR when PALB2 binding is present.…”

Section: Introductionmentioning

confidence: 99%

Plasticity of BRCA2 Function in Homologous Recombination: Genetic Interactions of the PALB2 and DNA Binding Domains

et al. 2011

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The breast cancer suppressor BRCA2 is essential for the maintenance of genomic integrity in mammalian cells through its role in DNA repair by homologous recombination (HR). Human BRCA2 is 3,418 amino acids and is comprised of multiple domains that interact with the RAD51 recombinase and other proteins as well as with DNA. To gain insight into the cellular function of BRCA2 in HR, we created fusions consisting of various BRCA2 domains and also introduced mutations into these domains to disrupt specific protein and DNA interactions. We find that a BRCA2 fusion peptide deleted for the DNA binding domain and active in HR is completely dependent on interaction with the PALB2 tumor suppressor for activity. Conversely, a BRCA2 fusion peptide deleted for the PALB2 binding domain is dependent on an intact DNA binding domain, providing a role for this conserved domain in vivo; mutagenesis suggests that both single-stranded and double-stranded DNA binding activities in the DNA binding domain are required for its activity. Given that PALB2 itself binds DNA, these results suggest alternative mechanisms to deliver RAD51 to DNA. In addition, the BRCA2 C terminus contains both RAD51-dependent and -independent activities which are essential to HR in some contexts. Finally, binding the small peptide DSS1 is essential for activity when its binding domain is present, but not when it is absent. Our results reveal functional redundancy within the BRCA2 protein and emphasize the plasticity of this large protein built for optimal HR function in mammalian cells. The occurrence of disease-causing mutations throughout BRCA2 suggests sub-optimal HR from a variety of domain modulations.

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Molecular Biology Basics in the “Omics” Era: Cancer Pathology

Surve

Idowu

2015

Molecular Oncology Testing for Solid Tumors

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BRCA2: safeguarding the genome through homologous recombination

Cited by 3 publications

References 88 publications

Failed gene conversion leads to extensive end processing and chromosomal rearrangements in fission yeast

Failed gene conversion leads to extensive end processing and chromosomal rearrangements in fission yeast

Plasticity of BRCA2 Function in Homologous Recombination: Genetic Interactions of the PALB2 and DNA Binding Domains

Molecular Biology Basics in the “Omics” Era: Cancer Pathology

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