Replication bypass model of sister chromatid exchanges and implications for Bloom's syndrome and Fanconi's anemia

A model of the sister chromatid exchange (SCE) process is outlined as a replication mechanism to bypass DNA crosslinks. The model suggests that when normal bidirectional replication advances from both sides towards a crosslink along the two opposite parental strands, the complementary parental strand segments can be temporarily displaced at each contralateral 5' side from the crosslink. The free ends produced in this first step will be terminally aligned but will have opposite polarity. The second step of the bypass can, however, be completed by either of two rejoining processes--terminal ligation of the free ends via nascent Okazaki pieces or aberrant complementation by overlapping the free ends. This bypass mechanism (1) allows replication to continue past a crosslink leaving it intact but (2) results in the switching of parental strands and their attached incomplete nascent strands above and below the crosslink site producing an exchange between sister chromatids. This model is compatible with the findings of current SCE studies using the new BUDR/stain techniques as well as with previous autoradiographic studies. It also suggests that the chromatid breaks and deletions in Fanconi's Anemia represent a defect in step two of the replication bypass mechanism and that the high frequency of SCE's and quadriradials in Bloom's Syndrome represent the SCE overload effects of a defect in crosslink repair.