There is a growing list of cancer-related proteins, many of which have a tumour suppressive function, that either interact with, or constitute the ubiquitin ligation machinery of H2Bub1, including RNF20 and RNF40, p53, BRCA1, CDC73, members of the SWI/SNF chromatin remodelling complex, members of histone methyltransferase complexes involved in cross-talk with H2Bub1 including DOT1L and COMPASS, and numerous deubiquitinases including USP22 and USP44 (Figure 1). The gene discussed is USP22; the disease is cancer.