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DNA DAMAGE REPAIR

The key to the FANCD2–FANCI lock

Nature Structural & Molecular Biology volume 29, pages 848–849 (2022)Cite this article

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New cryo-EM structures of the FANCD2–FANCI complex provide insights into how phosphorylation of FANCI facilitates DNA clamping to prime the complex for monoubiquitination and recruitment of downstream factors in the Fanconi anemia pathway of DNA damage repair.

DNA interstrand crosslinks (ICLs), induced by endogenous and exogenous agents, covalently link complementary DNA strands and thus pose a strong roadblock to DNA replication and transcription1. As such, these agents are highly cytotoxic and genotoxic, and chemicals that induce ICLs have been widely used as cancer therapeutics to exploit the susceptibility of tumor cells resulting from their high proliferative potential. Analysis of cells derived from the multigenic cancer-disposition syndrome Fanconi anemia (FA) and proteins encoded by the FA-associated genes has unveiled a mechanistically intricate mechanism of ICL repair mediated by these FA factors. Mutations in any of the 20+ FA genes (groups A to W) manifest clinically as developmental defects, bone marrow failure and a strong predisposition to certain cancers, such as acute myeloid leukemia1. Notably, the exquisite sensitivity of FA cells to ICL-causative agents remains the gold standard diagnostic test for the disease.

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Fig. 1: FANCD2–FANCI padlock.

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Acknowledgements

Studies in the authors’ laboratory are supported by research grants R01 CA168635, PO1 CA92584 and R35 CA241801 from the US National Institutes of Health and by a Team Science Grant from the Gray Foundation under the Basser BRCA Initiative. C.M.R. is the recipient of a postdoctoral fellowship from the American Cancer Society (PF-22-034-01-DMC; https://doi.org/10.53354/pc.gr.153716). P.S. is the holder of the Robert A. Welch Distinguished Chair in Chemistry (AQ-0012) and recipient of a Recruitment of Established Investigators Award from the Cancer Prevention and Research Institute of Texas (RR180029).

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  1. Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA

    Cody M. Rogers & Patrick Sung

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  1. Cody M. Rogers
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Correspondence to Patrick Sung.

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Rogers, C.M., Sung, P. The key to the FANCD2–FANCI lock. Nat Struct Mol Biol 29, 848–849 (2022). https://doi.org/10.1038/s41594-022-00826-3

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