PWWP2A is a chr5-binding protein that functions as an adapter between histone modifications/variants and chr5-modifying complexes. It contains a conserved PWWP domain and binds multivalently to H2A.Z-containing nucleosomes and H3K36me3-marked chr5, with particular enrichment at promoters of highly transcribed genes 12. PWWP2A competes with MBD3 and CHD4 for interaction with MTA1, forming a variant NuRD subcomplex (M1HR containing MTA1:HDAC1/2:RBBP4/7) that excludes the full NuRD complex 324. This variant complex recruits HDACs to regulate histone acetylation dynamics at active genes, promoting transcriptional elongation and preventing spurious initiation 3. PWWP2A is essential for proper mitosis progression and neural crest development, as its depletion impairs cell proliferation through mitotic delay and causes cranial-facial defects 1. Beyond its core chr5 function, circular RNA derived from PWWP2A (circ-PWWP2A) acts as a miRNA sponge, sequestering miR-203 and miR-223 to modulate TGF-β signaling and hepatic fibrosis 56. Novel PWWP2A gene fusions with kinases (e.g., PWWP2A::RET) have been identified in mesenchymal tumors, indicating potential disease relevance 7.