Key Protein Found to Be Guardian of Genome Stability

DNA replication. Red and green: replication regions. (Jordi Bernués, IRB Barcelona)

(CN) – Scientists have finally determined why histone 1 – a protein in cell nuclei – is a major form of protection against genomic instability and vital for organisms in general.

Reporting Friday in the journal Nature Communications, a team of researchers found that the suppression of histone 1 causes potentially fatal cell and DNA damage.

The team also determined that the deregulation of a commonly suppressed region of chromatin, known as heterochromatin, produces defects in information transcription. This disruption fosters the accumulation of DNA and RNA hybrids, or R-loops – a three-stranded nucleic acid structure that, when unscheduled, can cause damage by a number of different mechanisms. R-loops can be lethal.

“Although histone 1 is key component of chromatin – the form in which DNA is packaged inside the cell nucleus through the action of histones – there are still many questions open regarding this molecule,” said lead author Ferran Azorin, a professor at the Institute for Research in Biomedicine (IRB) in Barcelona, Spain. “Regarding the other histones, which are major proteins in the regulation of gene expression, we know which enzymes modify them, their functions, and how they are regulated.

“But for some reason, the functions of histone 1 have not been addressed.”

Jordi Bernues, a researcher at IRB Barcelona and co-author of the study, added that in the presence of histone 1, the team observed that genomic issues did not arise in spite of heterochromatin expression.

“The deregulation of heterochromatin has disastrous consequences,” Bernues said. “Histone 1 not only serves as a repressor but also actively contributes to the removal of R-loops.”

However, the team does not know how this function materializes.

“The mechanism is what we want to study, how histone 1 prevents the mechanism from causing damage,” said co-lead author Anna Casas-Lamesa, a doctoral student at IRB Barcelona.

Drosophila without wings. The removal of histone 1 causes the death of all cell precursors of this tissue. (Jordi Bernués, IRB Barcelona)

In order to evaluate the impact of histone 1 suppression, the team removed the precursor structure of wings in the fruit fly Drosophila melanogaster, a common research subject across multiple scientific disciplines. Only one variant of histone is present in the fly, whereas humans have up to seven, which simplified their research.

The fly also enabled the scientists to remove a protein from a specific region at a certain time. The team removed histone 1 from the preceding structure of wings. They observed that flies were born without wings, suggesting that the removal of histone 1 causes the death of all cell precursors of this tissue. If histone 1 were removed from the entire fly, the embryo would die, the team added.

A statistical analysis of gene expression also allowed the team to disprove a long-standing theory that histone 1 is a global repressor of gene expression.

“The effect of removing histone 1 on gene expression is very weak,” said Bernues.

Expression of the protein alters “only” 5 percent of genes.

Heterochromatin contains genetic information that is not translated for proteins but instead features closely regulated repetitive sequences that the cell silences.

Drosophila polytene chromosome. In yellow, the chromocenter region where heterochromatin is accumulated. (Jordi Bernués, IRB Barcelona)

“Both R-loops and the information held in heterochromatin have natural functions but when they are deregulated they are lethal,” Bernues said. “We have now been able to associate genomic instability with the uncontrolled formation of R-loops caused by the lack of histone 1 and this is completely new.”

Preliminary tests in cultured tumor cells also confirm that genomic instability is partially caused by histone 1 deficiency. However, further analysis of the functions of histone 1 is necessary, and researchers must identify associated proteins, as well as determine the specific enzymes that modify it and why. Additionally, future research should aim to map the cell-signaling pathways involved, according to the team.

Besides exploring the mechanisms through which the protein keeps heterochromatin in check, preventing R-loop formation, Casas-Lamesa is also researching the involvement of histone 1 in cancer.

“Our preliminary studies are promising,” Azorin said. “But we are still a long way off proposing histone 1 as a target.”

 

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