Newswise — Osaka, Japan – While developing a computer program, coding mistakes can lead to software bugs. Likewise, errors in our body's genetic code, DNA, housed within structures called chromosomes, can trigger alterations in the body. These alterations are responsible for numerous fatal illnesses, including cancer. Presently, Japanese researchers have unveiled fresh insights into a specific kind of genetic alteration: extensive chromosomal reconfiguration (ECR).
In an article published in Communications Biology, a team of researchers from multiple institutions, led by scientists from Osaka University, conducted an analysis on fission yeast to discover two crucial genes associated with the mechanism of ECR.
The scientists were particularly focused on studying the centromere, a crucial region responsible for the separation of chromosomes during cell division. The centromere consists of repetitive DNA sequences, and it is known that ECR tends to happen in regions with repeated DNA sequences. Rad51, an essential enzyme involved in DNA recombination and the exchange of genetic material, was of specific interest. Surprisingly, contrary to expectations, Rad51 actually inhibits rather than facilitates ECR at the centromere. The mechanism by which ECRs occur using the centromere repeat remains mysterious.
"By inducing mutations in Rad51-deficient yeast, which are known to have elevated GCR levels, we aimed to identify genes associated with GCR occurrence," explained senior author Takuro Nakagawa. "We observed cells with decreased GCR levels and identified mutations in the Srr1 and Skb1 genes. This finding suggests that these genes are involved in the occurrence of GCR."
Subsequently, the researchers proceeded to delete the Srr1 and Skb1 genes in Rad51-deficient yeast and assessed the occurrence of GCR. The cells lacking Srr1 as well as those lacking Skb1 demonstrated decreased rates of GCR. Furthermore, cells lacking both Srr1 and Skb1 exhibited even lower rates of GCR.
Lead author Piyusha Mongia explained, "Through our analysis, we discovered that Srr1 and Skb1 are implicated in the formation of isochromosomes, a specific type of structural mutation found in chromosomes. Deletion of either Srr1 or Skb1 resulted in a significant decrease in the occurrence of isochromosomes."
The findings of the research team mark a significant advancement in unraveling the mechanisms that drive GCR at the centromere. Since GCRs are implicated in various genetic disorders, including cancer, gaining insights into the process of GCR formation has the potential to enhance our capacity to treat specific genetic diseases. This represents a crucial step forward in our understanding of GCR and its broader implications for human health.
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The article, “Fission yeast Srr1 and Skb1 promote isochromosome formation at the centromere,” will be published in Communications Biology at DOI: https://doi.org/10.1038/s42003-023-04925-9
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