Binding of BAP1 to the BRCA1:BARD1 heterodimer disrupts the BRCA1:BARD1 association and consequently inhibits its E3 ubiquitin ligase activity. Downregulation of BAP1 expression results in the hypersensitivity of cells to ionizing radiation and in retardation of S phase progression, suggesting that BAP1 coordinates the enzymatic activity of the BRCA1:BARD1 complex during DNA double strand break response and during cell cycle (Nishikawa et al. 2009). While BAP1 is a deubiquitinating enzyme and may deubiquitinate some BRCA1:BARD1 substrates, it does not deubiquitinate autoubiquitinated BRCA1 and BARD1 (Mallery et al. 2002, Nishikawa et al. 2009). A catalytically-inactive mutant of BAP1, BAP1 C91S, is still able to inhibit BRCA1:BARD1-mediated ubiquitination, implying that BAP1 primarily regulates the action of the BRCA1:BARD1 complex by disrupting it (Nishikawa et al. 2009).