Unresolved lesions in mitosis are processed into ultrafine DNA bridges.
Failure to process joint DNA molecules in mitosis leads to persistent entangling of sister chromatids, generating ultrafine DNA bridges (UFBs) as cells progress into anaphase. Pulling force from mitotic spindle stretches the DNA, initiating binding of the PICH translocase to double-stranded DNA (dsDNA) regions of the UFB, and subsequent recruitment of the BTR (BLM, TOP3A, RMI1/2) complex and RIF1. RIF1 may interact with its effector protein phosphatase 1 (PP1), dephosphorylating PICH and BLM. The BLM helicase becomes activated and unwinds dsDNA into ssDNA, triggering localization of the RPA trimeric complex. Topoisomerase TOP3A may in turn decatenate ssDNA stretches to mediate resolution of UFBs. ‘C-UFB’ = centromeric UFB, ‘HR-UFB’ = homologous recombination UFB, ‘FS-UFB’ = fragile site UFB.