10 August 2012

New insights into genome integrity maintenance - another piece of the puzzle.

Important new insights into the cellular regulation of DNA repair mechanisms.

The integrity of the genome is continuously challenged by both endogenous and exogenous DNA damaging assaults. Unrepaired DNA double-strand breaks are particularly hazardous to the cell because, if not instantly lethal, they can lead to genome rearrangements. To prevent this, cells mobilize chromatin surrounding the DNA lesions to accumulate a multitude of repair and signalling proteins that cooperate to restore the integrity of the damaged genome. Prominent among such modifications is histone ubiquitylation triggered by a complex cascade of enzymatic reaction including RNF168, an E3 ubiquitin ligase that amplifies ubiquitin reactions specifically at damaged chromosomes. Although beneficial for DNA repair, it is crucial that this ubiquitinylation activity is confined to the site of the DNA lesion leaving the undamaged chromosomes untouched. Otherwise, an excessive chromatin ubiquitylation and spreading away from the site of damage could have far-reaching deleterious consequences in the healthy parts of the genome. In their new study, Jiri Lukas and his colleagues screened the human ubiquitinome for suppressors of RNF168 and identified two E3 ligases, TRIP12 and UBR5, that regulate RNF168 stability and thereby supress excessive chromatin ubiquitylation in cells challenged by DNA breakage.

Apart from uncovering a molecular pathway, which guards against illegitimate spreading of repair-associated enzymatic reactions, this study has implications for cancer research by showing that hyperaccumulation of RNF168 is a frequent ‘molecular signature’ of cancers associated with oncogenic human papillomaviruses. In addition, earlier studies reported TRIP12 and UBR5 mutations in other types of human malignancies, and it would be interesting to build on the new findings and investigate whether excessive chromatin ubiquitylation in such cases contributes to cancer progression. Please follow this link for a graphical abstract: http://www.cell.com/abstract/S0092-8674(12)00883-5.