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Fig. 1. Heterochromatin suppresses global chromosomal rearrangements mediated by centromere repeats. Credit: University of Osaka
Although many people know that chromosome damage and shortening contribute to the aging process, understanding how chromosomal defects occur is not just about finding a way back. Large changes in chromosome structure, called global chromosomal rearrangements, can lead to cell death or genetic diseases such as cancer.
Heterochromatin is a more coiled version of chromatin, the mbad of DNA and protein that forms chromosomes. A single region of a chromosome called the centromere is essential to the proper segregation of chromosomes during cell division. Although researchers have long known that centromeres are composed of heterochromatin, the reason why the centromere is so tight and how it helps to stabilize the region has remained elusive, until now.
In a recent article published in Biology of communicationA research team led by Osaka University revealed the role of heterochromatin in maintaining chromosomal integrity.
The centromeric regions contain a large number of short and repeated DNA sequences. These repetitions make the centromer particularly vulnerable to breakage and rearrangement, often resulting in the loss of an entire arm of one chromosome while the other arm is duplicated, forming structures called isochromosomes. But the Osaka University team discovered that a specific feature of methylation of histone H3, lysine 9 (H3K9) by heterochromatin, suppresses general chromosomal rearrangements caused by centromere repeats.
Fig. 2. The loss of histone H3K9 methyltransferase from the hormone Clr4 / Suv39 increases the spontaneous rate of global chromosomal rearrangements. Credit: University of Osaka
"The suppression of Clr4, the protein responsible for the methylation of H3K9 in the model organism Schizosaccharomyces pombe, has resulted in an increase in the formation of isochromosomes with localized breakpoints in centromere repeats," says lead author Akiko Okita, suggesting that methylation helps prevent rearrangements.
However, further investigation revealed that the mechanism was even more complex than expected.
Heterochromatin silences the action of RNA polymerase II, an enzyme responsible for the copy of DNA in RNA transcripts. Unexpectedly, complete silence of RNA transcription did not seem necessary to suppress global chromosomal rearrangements. The Tfs1 / TFIIS transcription factor is needed to revive RNA polymerase II if it goes back and forth along the already copied DNA sequence. Curiously, the researchers found that suppression of Tfs1 / TFIIS was sufficient to circumvent the need for Clr4 in suppressing global chromosomal rearrangements, and that RNA transcription levels were largely not affected by the removal of Tfs1 / TFIIS.
Fig. 3. A model describing how Tfs1 / TFIIS-dependent "persistent" transcription causes global chromosomal rearrangements mediated by centromere repeats. Credit: University of Osaka
"The results showed that persistent transcriptional repression of Tfs1 / TFIIS-dependent centromere repeats is the key role of heterochromatin in suppressing global chromosomal rearrangements," explains Dr. Corresponding author, Takuro Nakagawa. Heterochromatin essentially prevents repeated copies from being copied and used in the formation of global chromosomal rearrangements.
"We anticipate that our discoveries will help develop methods of securing genome integrity by manipulating chromatin status rather than by altering the DNA sequence," said Dr. Nakagawa. . "This would be a huge feat because the ability to suppress global chromosomal rearrangements is integral to preventing diseases resulting from chromosomal instability."
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More information:
Akiko K. Okita et al. Heterochromatin suppresses global chromosomal rearrangements at the centromere by repressing Tfs1 / TFIIS-dependent transcription, Biology of communication (2019). DOI: 10.1038 / s42003-018-0251-z
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