Identification of genes linked to chromosomal mutation through yeast screening

When creating a computer program, errors in the code can cause errors in the program. Similarly, errors in our body’s genetic code, DNA, stored in structures known as chromosomes, can cause mutations in the body. These mutations are the cause of many deadly diseases – including cancer. Now, researchers in Japan have shed new light on a specific type of genetic mutation: gross chromosomal rearrangements (GCR).

In a new study published in Communication biologyA multi-institutional team led by researchers from Osaka University analyzed fission yeast to identify two key genes involved in the GCR process.

The researchers were particularly interested in the centromere, an important region for chromosome segregation during cell division. The centromere contains repeated DNA sequences, and GCR is known to occur in regions where DNA sequences are repeated. Rad51 is a key enzyme involved in DNA recombination that exchanges genetic material. Contrary to what one might expect, Rad51 represses rather than promotes GCR at the centromere. It is mysterious how GCRs occur using centromere repeats.

“To find genes involved in GCR occurrence, we introduced mutants into yeast that lack Rad51, which show increased levels of GCR,” says senior author Takuro Nakagawa. “We looked for cells that showed lower levels of GCR and found that cells with mutations in the genes Srr1 and Skb1 had lower GCR, suggesting that these genes play a role in the occurrence of GCR.”

The researchers then deleted the Srr1 and Skb1 genes in yeast lacking Rad51 and assessed the occurrence of GCR. Srr1-deficient cells and Skb1-deficient cells showed reduced rates of GCR; Cells lacking both genes showed lower rates of GCR.

“Our analysis revealed that Srr1 and Skb1 are involved in the formation of isochromosomes, a type of structural mutation in the chromosome,” says lead author of the study Piyusha Mongia. “Loss of Srr1 or Skb1 greatly reduced the number of chromosomal homologues that occurred.”

The research team’s findings represent an important step toward understanding the mechanisms underlying GCRs at the centromere. As GCRs are implicated in many genetic disorders, including cancer, understanding the process of GCR formation may advance our ability to treat certain genetic diseases.