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. Author manuscript; available in PMC: 2013 Dec 11.
Published in final edited form as: FEBS Lett. 2011 May 19;585(18):10.1016/j.febslet.2011.04.078. doi: 10.1016/j.febslet.2011.04.078

Figure 1.

Figure 1

Ubiquitylation in response to interstrand crosslinks, highlighting Fanconi anemia proteins and the associated factors necessary for repair. Particular attention is drawn to some of the unknown factors in interstrand crosslink repair. A. Interstrand crosslinks prevent separation of the DNA helix. During replication this can lead to replication fork collapse when forks encounter lesions from one or both directions. For a full model of DNA transactions, see [63, 64]. This leads to RPA-ssDNA binding and activation of the ATR and the downstream DNA damage response B. Activation of the ID complex. ATR phosphorylates many FA proteins including FANCI. FANCI phosphorylation acts as a molecular switch in the FA pathway. The FA core complex is recruited to chromatin at sites of damage where it functions as an E3 ubiquitin ligase to monoubiquitylate the ID complex at the damage site. It is currently unknown if there are other substrates for ubiquitylation by the FA core complex. C. UBZ domain containing effectors. Downstream effectors FAN1, SLX4, and SNM1A harbor ubiquitin-bindingmotifs that are thought to target them to the site of damage through ubiquitin mediated interactions. FAN1 binds the monoubiquitylated FANCD2. SLX4 displays binding affinity for ubiquitin chains though the docking sites for SLX4 are not currently known. SLX4 could potentially interact with ubiquitylated FANCD2 or PCNA. Interestingly all three proteins harbor nuclease activity or are associated with nucleases. Thus, control of ubiquitylation events regulates the localization of nucleases at the site of damage. One of the remaining questions is why there are so many nucleases at the repair sites. D. Translesion synthesis step. Chromatin bound PCNA is monoubiquitylated by RAD18 in response to interstrand crosslinking damage and coordinates translesion synthesis steps during interstrand crosslink repair. Additional, non-PCNA and non-RAD18-dependent events are likely to allow translesion synthesis to occur. D. Homologous recombination (HR) concludes the repair process. FA proteins BRCA2, PALB2, and the Fanconi anemia-like syndrome protein RAD51C are involved in this step. FANCJ is also important for HR but in the context of FA, it clearly has other functions, which are not yet fully explored.

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