Fig. 6: Model for the effect of the BLM-condensin II interaction on genome stability.

a Model of how BLM binding to condensin II increases efficiency of detection and repair of BLM substrates. Current models of loop extrusion posit that the hinge domain reels in new DNA through the SMC2-SMC4 lumen creating an intermediate loop with gate opening potentially allowing the intermediate loop to join the main loop^50,72,74,106. BLM, through its interaction with condensin II at the WMF site, can scan this intermediate loop for its substrates such as R-loops, DNA breaks, or G-quadruplexes, leading to their resolution prior to becoming an impediment to the replication or transcription machinery, thus mediating normal DNA transactions and genome stability. The many DNA repair and replication factors that bind to BLM’s disordered tail likely contribute to resolution and repair. In the absence of BLM from condensin II due to the WMF mutation, the DNA lesions and replisome blocks are not resolved efficiently, thus increasing risk of collisions with the replisome or transcriptional machinery, leading to impaired replisome progression and fork stalling, impaired DNA-damage response, delayed DSB repair and, eventually, mitotic chromosome aberrations. Created in BioRender. Rodemoyer, B. (2025) https://BioRender.com/h40u746. b Model of how BLM-condensin II interaction may contribute to suppression of crossovers. Extrusion of adjacent loops may aid BLM helicase-mediated branch migration of Holliday junctions between sister chromatids. BLM-condensin II interaction puts BLM in close proximity to the HR intermediate, increasing efficiency of dissolution as noncrossovers (NCO) in cooperation with interacting proteins. Loss of BLM-condensin II interaction due to BLM-WMF^mut reduces dissolution of HR intermediates by BLM complexes and increases resolution via cleavage by structure-specific endonucleases, causing crossovers (CO). Created in BioRender. Rodemoyer, B. (2025) https://BioRender.com/k17g890.