Dual roles of UFMylation on stalling fork stability

The mechanism governing the stabilization of the replication fork under replication stress is pivotal for maintaining genomic integrity and cellular viability. In this context, the safeguard factors BRCA1/2 and nucleases engage in a regulatory equilibrium, modulating the extent of nascent strand end resection—a process vital for replication fork stabilization under stress and for fork restart upon stress released. The recruitment dynamics of these nucleases, however, remain to be elucidated. Recent two independent studies by Gong et al. and Tian et al. have demonstrated that ubiquitin-like modification UFMylation employs dual pathways to facilitate the recruitment of nuclease MRE11, integral to the fork reversal mechanism. These revelations uncover novel roles of UFMylation in genome stability and provide guidance in identifying novel targets for treating BRCA1/2-mutated tumors.