Aberrations of both TRIP12 and UBR5 have been described in certain types of cancer (Clancy et al., 2003; O’Brien et al., 2008; Yoo et al., 2011), and elevated RNF168 protein levels and expanded 53BP1 foci were found in a subset of advanced human papillomavirus (HPV)-positive tumors (Gudjonsson et al., 2012), suggesting that the homeostasis of ubiquitin signaling achieved through regulation of RNF168 levels as illustrated here could be subverted during tumorigenesis. Here, UBR5 is linked to cancer.