Genome complexity: DNA repair mechanisms (Introduction)

by David Turell , Sunday, October 25, 2015, 12:54 (3106 days ago) @ dhw

Histone 1 now added to the repair mechanism. Histones 2-5 were previously known to signal for repair:-http://www.nature.com/nature/journal/vaop/ncurrent/full/nature15401.html-"DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions that trigger non-proteolytic ubiquitylation of adjacent chromatin areas to generate binding sites for DNA repair factors. This depends on the sequential actions of the E3 ubiquitin ligases RNF8 and RNF168 (refs 1, 2, 3, 4, 5, 6), and UBC13 (also known as UBE2N), an E2 ubiquitin-conjugating enzyme that specifically generates K63-linked ubiquitin chains7. Whereas RNF168 is known to catalyse ubiquitylation of H2A-type histones, leading to the recruitment of repair factors such as 53BP1 (refs 8, 9, 10), the critical substrates of RNF8 and K63-linked ubiquitylation remain elusive. Here we elucidate how RNF8 and UBC13 promote recruitment of RNF168 and downstream factors to DSB sites in human cells. We establish that UBC13-dependent K63-linked ubiquitylation at DSB sites is predominantly mediated by RNF8 but not RNF168, and that H1-type linker histones, but not core histones, represent major chromatin-associated targets of this modification. The RNF168 module (UDM1) recognizing RNF8-generated ubiquitylations11 is a high-affinity reader of K63-ubiquitylated H1, mechanistically explaining the essential roles of RNF8 and UBC13 in recruiting RNF168 to DSBs. Consistently, reduced expression or chromatin association of linker histones impair accumulation of K63-linked ubiquitin conjugates and repair factors at DSB-flanking chromatin. These results identify histone H1 as a key target of RNF8-UBC13 in DSB signalling and expand the concept of the histone code12, 13 by showing that posttranslational modifications of linker histones can serve as important marks for recognition by factors involved in genome stability maintenance, and possibly beyond."-***-http://www.sciencedaily.com/releases/2015/10/151023145114.htm-"Histones enable the tight packaging of DNA strands within cells. The strands are two metres in length and the cells usually approx. 100,000 times smaller. Generally speaking, there are five types of histones. Four of them are so-called core histones, and they are placed like beads on the DNA strands, which are curled up like a ball of wool 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 possibly damaged DNA.-"The four core histones have so-called tails, and among other things they 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 so-called mass spectrometer, a technique developed in collaboration with fellow researchers at the Novo Nordisk Foundation Centre for Protein Research, Niels Mailand and his team have discovered that, surprisingly, 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," Niels Mailand elaborates."-Comment: Ever more complex and with the appearance of 'cleverly planned'. How much evidence is needed before 'design' is accepted?