Mechanism behind suppression of chromosome abnormality by homologous recombination (HR) enzyme Rad51
A step toward the development of drugs for treating breast cancer
There are various types of repetitive sequences in the living organism genome, but curiously enough, nearly half of the human genome is occupied by such repetitive sequences. In recent years, it has been clarified that chromosome abnormality is caused by these repetitive sequences, developing cancer or genetic diseases. If there are mutations in human BRCA (breast cancer susceptibility gene) 1 or BRCA2, both of which are also involved in homologous recombination like Rad51, chromosome abnormality frequently takes place, increasing the risk of developing breast and ovary cancers. From this, it is thought that maintaining chromosomes by homologous recombination is important in delaying the onset of cancers; however, how homologous recombination prevents chromosome abnormality is not known.
A group of researchers led by Associate Professor NAKAGAWA Takuro, Professor MASUKATA Hisao, Assistant Professor TAKAHASHI Tatsuro, and graduate student ONAKA Atsushi at the Graduate School of Science, Osaka University, in experiments using a model organism for chromosome research, fission yeast, clarified that the onset of chromosome abnormality mediated by crossover recombination caused by Mus81 could be prevented if homologous recombination enzymes Rad51 and Rad54 promoted non-crossover recombination between repetitive sequences.
It’s important for living organisms to maintain chromosomes that carry genetic information. Once chromosome abnormality mediated by recombination in inverted repetitive sequence in the centromere of chromosome occurs, isochromosomes, in which the arms of chromosomes are mirror images of each other, are formed. This group clarified that homologous recombination enzymes Rad51 and Rad54 facilitated local recombination, or non-crossover recombination, in repetitive sequences, whereas they inhibited the formation of crossover recombination and isochromosomes in repetitive sequences.
It was believed that Rad51 was essential for homologous recombination; however, this study shows the possibility that crossover recombination takes place even when Rad51 is not present, thereby causing chromosome abnormality. In order to verify this hypothesis, this group disrupted DNA cleavage enzyme Mus81 in Rad51-deficient cells and found that crossover recombination that had been observed in Rad51-deficient cells decreased and the frequency of developing chromosome abnormality dropped as well. From this, it is thought that Rad51 and Rad54 selectively cause non-crossover recombination to prevent chromosome abnormality.
The discovery of a Mus81-specific inhibitor will lead to the development of cancer therapy and prevention for patients who have mutations in BRACA1 and BRCA2.
Abstract
Centromeres consist of DNA repeats in many eukaryotes. Non-allelic homologous recombination (HR) between them can result in gross chromosomal rearrangements (GCRs). In fission yeast, Rad51 suppresses isochromosome formation that occurs between inverted repeats in the centromere. However, how the HR enzyme prevents homology-mediated GCRs remains unclear. Here, we provide evidence that Rad51 with the aid of the Swi/Snf-type motor protein Rad54 promotes non-crossover recombination between centromere repeats to prevent isochromosome formation. Mutations in Rad51 and Rad54 epistatically increased the rates of isochromosome formation and chromosome loss. In sharp contrast, these mutations decreased gene conversion between inverted repeats in the centromere. Remarkably, analysis of recombinant DNAs revealed that rad51 and rad54 increase the proportion of crossovers. In the absence of Rad51, deletion of the structure-specific endonuclease Mus81 decreased both crossovers and isochromosomes, while the cdc27/pol32-D1 mutation, which impairs break-induced replication, did not. We propose that Rad51 and Rad54 promote non-crossover recombination between centromere repeats on the same chromatid, thereby suppressing crossover between non-allelic repeats on sister chromatids that leads to chromosomal rearrangements. Furthermore, we found that Rad51 and Rad54 are required for gene silencing in centromeres, suggesting that HR also plays a role in the structure and function of centromeres.
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To learn more about this research, please view the full research report entitled “ Rad51 and Rad54 promote noncrossover recombination between centromere repeats on the same chromatid to prevent isochromosome formation ” at this page of the Nucleic Acids Research website.
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