Molecular mechanisms of the Asx C-terminal region for genomic targeting of PR-DUB in Drosophila

This reaction requires interaction of the PR-DUB catalytic subunit Bap1 with the N-terminus of its partner Asx. In Drosophila, Asx truncation mutants lacking the C-terminal low-complexity region and PHD finger display severe PR-DUB loss-of-function phenotypes.

PR-DUB containing C-terminally truncated Asx retain deubiquitinase activity but fail to localize to Polycomb target genes, resulting in excessive H2Aub1 accumulation that disrupts repression. Unexpectedly, the conserved interaction between the Asx PHD finger and Mbd5 is dispensable for viability but fine-tunes H2Aub1 deubiquitination at a subset of Polycomb target genes. In contrast, a short domain in the Asx C-terminus that associates with the DNA-binding domain of the Polycomb protein Pho is essential for viability.