The FANCJ helicase unfolds DNA-protein crosslinks to promote their repair

Endogenous and exogenous agents generate DNA-protein crosslinks (DPCs), whose replication-dependent degradation by the SPRTN protease suppresses aging and liver cancer. SPRTN is activated after the replicative CMG helicase bypasses a DPC and polymerase extends the nascent strand to the adduct. Here, we identify a role for the 5′-to-3′ helicase FANCJ in DPC repair. In addition to supporting CMG bypass, FANCJ is essential for SPRTN activation. FANCJ binds ssDNA downstream of the DPC and uses its ATPase activity to unfold the protein adduct, which exposes the underlying DNA and enables cleavage of the adduct. FANCJ-dependent DPC unfolding is also essential for translesion DNA synthesis past DPCs that cannot be degraded. In summary, our results show that helicase-mediated protein unfolding enables multiple events in DPC repair. [Display omitted] •FANCJ unfolds DNA-protein crosslinks (DPCs)•FANCJ is required for SPRTN-mediated DPC proteolysis during replication•FANCJ is essential for translesion DNA synthesis past intact DPCs•FANCJ promotes bypass of covalent and non-covalent protein barriers When a DNA replication fork encounters a covalent DNA-protein crosslink (DPC), SPRTN cleaves the protein adduct to promote replicative bypass. Yaneva et al. show that the FANCJ helicase promotes SPRTN activity by unfolding the crosslinked protein. DPC unfolding by FANCJ also allows translesion DNA synthesis past non-degradable DPCs.