FIG 9.

Model describing the role of FAN1 at a stalled replication fork. (A) Role of FAN1 in the presence of FANCD2. MRE11 is recruited to APH-stalled replication forks first, followed by FANCD2 and its constitutive interaction partner, BLM. Nonubiquitinated FANCD2 and MRE11 then both support the recruitment of FAN1. Subsequently, all four proteins (likely in concert with other BLM complex members) act in concert to promote replication fork restart in a manner dependent on the MRE11 and FAN1 nuclease activities. Concurrent with efficient fork restart, the firing of new origins is suppressed. In addition, FANCD2 protects the nascent DNA strands from nucleolytic attack by MRE11 and FAN1 during replication fork stalling. (B) Role of FAN1 in the absence of FANCD2. MRE11 is recruited to APH-stalled forks and enables partial recruitment of FAN1 independently of FANCD2. Despite the presence of MRE11 and FAN1, replication forks cannot restart efficiently, which in turn triggers firing of new replication origins. At the same time, the absence of FANCD2 allows for uncontrolled access of MRE11 and FAN1 to DNA at the stalled fork, leading to nucleolytic degradation of nascent DNA strands behind the fork.