Post-translational modification of histone proteins plays a major role in histone-DNA packaging and gene expression. Attachment of ubiquitin at the C-terminal tail of histone H2A, H2AK119Ub in mammals, represses gene expression, and is removed by the Polycomb Repressive Deubiquitinase (PR-DUB) complex. The mammalian complex is comprised of the catalytic deubiquitinase BRCA1-associated protein 1 (BAP1) and regulatory Additional Sex Combs-like 1–3 (ASXL1–3). The basis for ASXL1–3 activating BAP1 is well-established. However, we hypothesize that an N-terminal, DNA-binding HB1, ASXL, and restriction endonuclease helix-turn-helix (HARE-HTH) domain and a C-terminal Plant Homeodomain (PHD) are required for localization. The ASXL PHD is poorly characterised but essential for proper PR-DUB activity — truncation of ASXL1–3 causes loss of the C-terminal PHD domain, and is commonly mutated in leukaemia, occurring in ~11% of hematopoietic cancers. Typically, PHD domains bind histone modifications to convey localisation. We have established that the ASXL PHD is atypical and previously mischaracterized. This domain is unable to bind histone modifications, as assessed by medium-throughput histone H3 modification ELISAs and Isothermal Titration Calorimetry. We propose an alternative role for the ASXL PHD based on high-throughput analysis of protein-protein interactions using proximity-dependent labelling coupled with Mass Spectrometry. Further proximity-ligation Mass Spectrometry along with chromatin localization sequencing are currently being used to study the protein-protein interaction network and DNA-binding capabilities of the N-terminal ASXL HARE-HTH domain. Together, these analyses will allow us to determine the role of the ASXL HARE-HTH in localisation, furthering our understanding of PR-DUB activity.