Regulation of TIPIN and replication fork dynamics by USP37

The deubiquitinating enzyme, USP37, is associated with control of replication and the replication stress response. Cells with oncogene-induced replication stress harbor elevated levels of USP37 and are more sensitive to its loss. These cells experience increased replication stress and delayed progression of the replication fork in the absence of USP37. Consistent with these observations, we find that USP37-deficient cells more frequently fail to restart stalled forks and that these forks are more susceptible to nuclease activity. Underlying these phenomena, we show that USP37 resides at the replication fork and associates with the replisome where it is able to act on TIPIN to promote its stable association with chromatin. These findings suggest the regulation of proteins at the replication fork contributes to fork function and underlies the requirement of cancer cells for USP37.