Regulation of p 53 stability and function by the deubiquitinating enzyme USP 42

Thank you for submitting your manuscript on USP42 as a new p53-stabilizing DUB for consideration by The EMBO Journal. It has now been assessed by three referees, who acknowledge the potential importance of these findings and would in principle also support eventual publication. Nevertheless, it is apparent from their comments that all of them feel that a deeper analysis of the USP42-p53 interplay and the underlying mechanisms will be required for EMBO J publication, in addition to clarifying a number of more specific technical points. In this respect, a key question is why USP42 selectively stabilizes p53 in response to stress signals, and how the interaction is modulated during the stress response. Another important issue is the clarification of how USP42 impinges on the p53/Mdm2 axis which would require p53 ubiquitination status analyses and comprehensive pulse-chase half-life measurements for not only p53 but also Mdm2 and p21, as detailed by the referees; in this respect, the question of why USP42 would be needed in Nutlin-3dependent p53 activation also becomes relevant. On the other hand, some issues we would consider less crucial within the scope of this study are the requests for USP42 isoform dissection or for assessing USP42 effects on other p53 pathway DUBs.