Bibliografisk note

Funding Information:
I thank the following sources for funding: the Novo Nordisk Foundation (grant nos. NNF14CC0001 and NNF18OC0030752), Lundbeck Foundation (grant no. R223-2016-281), Danish Cancer Society (grant no. R231-A13972), Independent Research Fund Denmark (grant nos. 7016-00055B and 0134-00048B), and Danish National Research Foundation (grant no. DNRF-115).

Funding Information:
Using Xenopus egg extracts to search for DNA helicases functioning alongside RTEL1 to help CMG overcome proteinaceous roadblocks, the authors first identify a role of FANCJ as an accessory helicase promoting CMG bypass of both DPCs and DPC-like non-covalent DNA-protein complexes. Notably, however, although depleting FANCJ from extracts led to an accompanying defect in DPC repair as expected, the team discovered that FANCJ is essential for SPRTN-mediated DPC cleavage even in repair contexts where the need for CMG bypass is obviated. Through a series of technically nifty experiments to elucidate the underlying mechanism, they provide several lines of evidence arguing collectively that FANCJ translocates into the DPC to effect its unfolding, thereby rendering the crosslinked protein susceptible to the proteolytic action of SPRTN (Figure 1C). For instance, under experimental conditions that prevent the refolding of a native DPC following heat denaturation, FANCJ becomes dispensable for SPRTN-mediated DPC cleavage, and limited proteolysis experiments support a direct role of FANCJ in unfolding the protein adduct. In the case of native DPCs, most of which likely involve DNA-binding proteins, the action of FANCJ may also help to expose the underlying DNA structure to allow SPRTN binding and activation, yet this does not seem to do away with the requirement for FANCJ to unfold the DPC. Replication-coupled DPC proteolysis is normally followed by replication past the peptide remnant by specialized damage-tolerant translesion DNA synthesis (TLS) polymerases (Figure 1D).2 Interestingly, the authors show that FANCJ is not required for this process per se but becomes essential for TLS when DPC proteolysis is blocked, suggesting that the unfolding of the protein adduct may facilitate its accommodation within the TLS polymerase active site. All these FANCJ functions require its ATPase activity, and a Fanconi anemia (FA)-associated FANCJ point mutant (A349P) exhibiting an impaired ability to unwind higher-order DNA structures and disrupt protein-DNA complexes7 fails to support SPRTN-mediated proteolysis of native DPCs in biochemical reconstitutions. Factoring in previous work showing that FANCJ contributes to replication-dependent unwinding of replisome-arresting G-quadruplex secondary DNA structures,8 an interesting model emerges in which FANCJ remodels both DNA- and protein-based impediments via force generation by its motor activity to serve as a key factor for overcoming diverse obstacles to replisome progression.The findings by Yaneva et al.1 suggest that the unfolding of the protein adduct is a prerequisite for proteolytic processing of at least some DPCs and reveal FANCJ as an important, if unexpected, component of the toolkit enabling this step of the repair process. This conclusion raises several questions. One obvious challenge will be to explain mechanistically how FANCJ ATPase activity can drive partial or extensive protein unfolding, which may ultimately require structural insights. Whether protein unfolding by a DNA translocase is unique to FANCJ or extends to other such enzymes also remains to be established. Moreover, how TLS polymerases seemingly manage the impressive feat of replicating across entire DPCs remodeled by FANCJ clearly merits further targeted exploration and showcases the remarkable flexibility of DNA damage repair and bypass mechanisms. The putative unfoldase function of FANCJ is analogous to the key role of the p97/VCP ATPase in unfolding ubiquitylated proteins to promote their proteasomal degradation. In fact, SPRTN directly interacts with p97, yet whereas some recent evidence suggests a role of p97 in SPRTN-dependent DPC repair in human cells,9,10 neither p97 binding nor DPC ubiquitylation is required for SPRTN's ability to cleave DPCs in Xenopus egg extracts,11 perhaps due to the action of FANCJ. Further interrogation of the division of labor between FANCJ and p97 unfoldase activities in different DPC repair contexts is thus warranted. Mutations in FANCJ are linked to FA and various cancers.8 As the aforementioned FA-associated FANCJ A349P mutant does not support SPRTN activation in vitro, understanding how FANCJ unfoldase activity contributes to DPC repair in mammalian cells and protection against human disease is an important, but undoubtedly demanding, future goal, considering the implication of FANCJ in multiple aspects of genome stability maintenance8 and potential redundancies with other helicases, including RTEL1. Given the unorthodox novel role of FANCJ in resolving DPCs, further revealing plot twists to the evolving saga of how these toxic lesions are dealt with by versatile mechanisms to maintain cell and organismal fitness may well be in store.I thank the following sources for funding: the Novo Nordisk Foundation (grant nos. NNF14CC0001 and NNF18OC0030752), Lundbeck Foundation (grant no. R223-2016-281), Danish Cancer Society (grant no. R231-A13972), Independent Research Fund Denmark (grant nos. 7016-00055B and 0134-00048B), and Danish National Research Foundation (grant no. DNRF-115). The author declares no competing interests.

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