Model: WT U2OS cells restart stalled replication forks at the telomere by HR-mediated fork restart or employ RAD52-dependent break induced replication upon replication fork collapse/cleavage (MUS81-independent). RAD52 acts as a strand annealing factor to promote POLD3-dependent conservative DNA synthesis. In the absence of EXD2, excessive replication fork regression mediated by SMARCAL1 leads to fork degradation and fork collapse by MUS81-dependent nucleolytic cleavage. This results in a fork conformation that is preferentially processed by the RAD52-independent arm of the ALT BIR mechanism, whereby an as-yet unidentified annealing factor promotes POLD3-dependent conservative DNA synthesis resulting in poor telomere elongation and the presence of T-SCEs. In the absence of factors that promote BIR-mediated ALT synthesis, collapsed replication forks at the telomere in EXD2-deficient cells cannot be efficiently repaired.
