Structural insights on the regulation of histone ubiquitination

Histone ubiquitination plays an essential role in the regulation of transcription initiation and elongation, and facilitates the DNA damage response and repair by promoting the recruitment of repair proteins. The relevance of this process is such that depleted global histone ubiquitination levels have been reported in several cancer types. Despite the intensive research on the histone ubiquitination machinery, its structure and the molecular mechanisms driving its specificity and regulation are still unclear. More importantly, the connections between an impaired machinery and the onset of these cancer types remain obscured. Thus, this project aims to structurally characterize the Histone ubiquitination machinery in complex with its nucleosome substrate and its regulatory proteins using cryo electron microscopy. Understanding the target recognition, modification and regulation at the molecular level will be instrumental to rationalize future therapeutic applications.