fork reversal pathway + representative picture
The human RECQ1 helicase and poly(ADP-ribose) polymerase (PARP1) regulate replication fork reversal. (Left) PARP poly(ADPribosyl)ation activity inhibits the fork restart function of RECQ1 until the damage (red triangle) is repaired. (Right) Representative electron micrograph showing the image of a reversed replication fork. D, daughter strand; P, parental strand; R, reversed arm.

Berti et. al, Nat. Struct. Mol Biol. 2013

Fork reversal is a central pathway in the replication stress response to DNA damaging chemotherapeutics that allows replication forks to cope with DNA lesions by reversing their course. We uncovered a key role of the human RECQ1 helicase in the restart of reversed replication forks. We also found that the fork restart function is regulated by poly(ADP-ribose) polymerase (PARP1), which suppresses RECQ1 activity until the damage is repaired, providing the first insight into the molecular steps that drive the timely resolution of reversed replication forks. Shortly thereafter, we identified a second human DNA2- and WRN-dependent mechanism of reversed fork processing and restart. We also found that depletion of the central recombinase RAD51 antagonizes this mechanism, presumably by preventing reversed fork formation. Collectively, our work provided the first mechanistic insight into how replication forks reverse and restart as a pivotal response to treatment with DNA damaging chemotherapeutics, and offers new molecular perspectives to potentiate current DNA-damaging chemotherapeutic regimens by targeting fork reversal.