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New Histone Function Identified: Histone H1 Couples Initiation and Amplification of Ubiquitin Signaling after DNA Damage; Finding May Improve Understanding of DNA Protection & Repair and Spawn New Disease Treatments

Researchers at the University of Copenhagen in Denmark, together with colleagues at the Netherlands Cancer Institute, have identified a previously unknown function of histone H1, one of the five known histones, which allows for an improved understanding of how cells protect and repair DNA damages. This knowledge may eventually result in better treatments for diseases such as cancer. "I believe that there's a lot of work ahead. It's like opening a door onto a previously undiscovered territory filled with lots of exciting knowledge. The histones are incredibly important to many of the cells' processes, as well as their overall well-being," says Dr. Niels Mailand from the Novo Nordisk Foundation Centre for Protein Research at the Faculty of Health and Medical Science. The findings were published online on October 21, 2015 in Nature. The article is titled “Histone H1 Couples Initiation and Amplification of Ubiquitin Signaling after DNA Damage.” Specifically, the researchers concluded that their results “identify histone H1 as a key target of [the E3 ubiquitin ligase RNF8 and the E2 ubiquitin-conjugating enzyme UBC13] RNF8–UBC13 in double-strand break (DSB) signalling and expand the concept of the histone code by showing that post-translational modifications of linker histones can serve as important marks for recognition by factors involved in genome stability maintenance, and possibly beyond.” Histones enable the tight packaging of DNA strands within cells. The strands are approximately two meters in length and the cells are usually approximately 100,000 times smaller. Generally speaking, there are five types of histones. Four of these types are so-called “core” histones, and they are placed like beads on the DNA strands, which are curled up like a ball of yarn within the cells. The role of the histones is already well described in research, and in addition to enabling the packaging of the DNA strands, they also play a central part in practically every process related to the DNA code, including repairing damaged DNA.

The four core histones have so-called tails, and they can signal damage to the DNA and thus attract the proteins that help repair the damage. Between the histone "yarn balls" we find the fifth histone, histone H1, but, up until now, its function has not been thoroughly examined.

Using a mass-spectrometry-based technique developed in collaboration with fellow researchers at the Novo Nordisk Foundation Centre for Protein Research, Dr. Mailand and his team have discovered that, surprisingly to them, the H1 histone also helps summon repair proteins.

"In international research, the primary focus has been on the core histones and their functionality, whereas little attention has been paid to the H1 histone, simply because we weren't aware that it too influenced the repair process. Having discovered this function in the H1 constitutes, an important piece of the puzzle of how cells protect their DNA, and it opens a door onto hitherto unknown and highly interesting territory," Dr. Mailand elaborates.

He expects the discovery to lead to increased research into the H1 histone worldwide, which will lead to increased knowledge of cells' abilities to repair damage to their DNA and thus increase our knowledge of the basis for diseases caused by cellular changes. It will likely also generate new insights into possible treatments of these diseases.

"The knowledge we generate can prove important to the development of more targeted treatments for diseases caused by cellular changes, including cancer. By mapping the function of the H1 histone, we will also learn more about the repair of DNA damages on a molecular level. In order to provide the most efficient treatment, we need to know how the cells prevent and repair these damages," Dr. Mailand concludes.

The image illustrates the structure of a nucleosome with double-stranded DNA (red) wrapped around core histones (grey spheres) and with histone H1 (vertical green) securing the DNA around the core histones.

[Press release] [Nature abstract]