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

Asx C-terminal truncations in Drosophila cause PR-DUB loss-of-function phenotypes by retaining deubiquitinase activity but preventing localization to Polycomb target genes, driving excessive H2Aub1 accumulation.

• Why it matters: Genomic targeting of PR-DUB is required to maintain Polycomb repression, yet how Asx’s C-terminal region directs PR-DUB to specific chromatin sites was unclear.
• What they did: Drosophila Asx truncation mutants lacking the C-terminal low-complexity region and PHD finger were analyzed for PR-DUB localization, H2Aub1 levels, and repression; Asx PHD–Mbd5 and Asx–Pho interactions were tested for their roles in viability and targeting.
• The result: The Asx–Pho interaction is essential for viability and recruits PR-DUB to most Polycomb target genes, promoting H2Aub1 deubiquitination and preserving repression, while Asx PHD–Mbd5 fine-tunes deubiquitination at a subset.