PDS5A is a regulatory protein of the cohesin complex that controls sister chr4 cohesion and three-dimensional genome organization 1. As a cohesin-associated factor, PDS5A stabilizes cohesin complex association with chr4 and regulates cohesin dynamics through multiple mechanisms 1. Mechanistically, PDS5A acts as a brake on chr4 loop extension by controlling cohesin acetylation and interaction states; acetylated cohesin bound to PDS5A restricts loop length, while HDAC8-mediated deacetylation promotes loop extension 2. PDS5A also localizes to loop anchors with RAD21 and CTCF, where it stabilizes cohesin recruitment and maintains proper loop architecture 3. Additionally, PDS5A maintains ultra-long Polycomb loops required for robust epigenetic silencing at target genes 4. Disease relevance is substantial: PDS5A mutations occur across myeloid malignancies including acute myeloid leukemia (AML) and myelodysplastic syndromes 56. PDS5A destabilization in AML compromises replication fork integrity and DNA replication fidelity 7. Clinically, PDS5A represents a potential therapeutic target in cohesin-dependent cancers, as its loss sensitizes cells to replication stress 7.