24 September 2012

CPR scientist’s provides new insight into ubiquitylation dynamics:

Thousands of DNA damaging insults are inflicted daily upon the genomes of all living cells. If left unrepaired, these lesions can be life-threatening for organisms as they alter the content and organization of the genetic material, jeopardizing cell and organismal survival and fitness. To mitigate this threat, cells have evolved a global DNA damage response (DDR), a sophisticated network of interconnected signaling pathways involving a large number of proteins, which cooperate to detect and repair DNA damage. Signaling in the DDR is largely driven by DNA damage-induced posttranslational modifications of numerous proteins. Protein modification with the small modifier protein ubiquitin has emerged as a key regulatory mechanism in many critical DNA damage signaling and repair pathways, but our insight into the the nature and scope of ubiquitin functions in the DDR is still limited.

In a new joint study published in Nature Cell Biology, the Mailand and Choudhary labs at the CPR now report the first proteome-wide analysis of DNA damage-regulated ubiquitylation in human cells, revealing extensive involvement of ubiquitin-dependent protein modifications in cellular signaling pathways that protect genome integrity in our cells. The study brings unprecedented new insight into the extent to which ubiquitin operates as a signaling mechanism in cellular responses to DNA damage, and opens up many new avenues for the continued exploration of the roles of ubiquitin in safeguarding genome stability.

This in turn is of key importance for understanding the molecular basis of a range of human malignancies resulting from genome alterations. From their global survey of DNA damage-regulated ubiquitylation, the authors also established a critical function of DNA damage-regulated ubiquitylation of the PAF15 protein in promoting DNA damage bypass, an important cellular means of preventing gross chromosomal instability.