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Regulation of Rev1 by the Fanconi anemia core complex

Nature Structural & Molecular Biology volume 19, pages 164–170 (2012)Cite this article

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Abstract

The 15 known Fanconi anemia proteins cooperate in a pathway that regulates DNA interstrand cross-link repair. Recent studies indicate that the Fanconi anemia pathway also controls Rev1-mediated translesion DNA synthesis (TLS). We identified Fanconi anemia–associated protein (FAAP20), an integral subunit of the multisubunit Fanconi anemia core complex. FAAP20 binds to FANCA subunit and is required for stability of the complex and monoubiquitination of FANCD2. FAAP20 contains a ubiquitin-binding zinc finger 4 domain and binds to the monoubiquitinated form of Rev1. FAAP20 binding stabilizes Rev1 nuclear foci and promotes interaction of the Fanconi anemia core with PCNA–Rev1 DNA damage bypass complexes. FAAP20 therefore provides a critical link between the Fanconi anemia pathway and TLS polymerase activity. We propose that the Fanconi anemia core complex regulates cross-link repair by channeling lesions to damage bypass pathways and preventing large DNA insertions and deletions.

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Figure 1: C1orf86 is required for Fanconi anemia pathway activation.
Figure 2: FAAP20 is required for stability of Fanconi anemia core complex.
Figure 3: FAAP20 interacts with Rev1 and promotes efficient Rev1 focus formation.
Figure 4: Monoubiquitination of Rev1 enhances interaction with FAAP20.
Figure 5: FAAP20 and Rev1 colocalize at sites of replication stress.
Figure 6: Branched model of Fanconi anemia pathway.

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Acknowledgements

We thank L.A. Moreau for chromosome aberration assay and K. Hofmann (Miltenyi Biotec), I. Dikic (Institute of Biochemistry II), A.R. Lehmann (University of Sussex), and E.H.-Y. Cheng (Memorial Sloan-Kettering Cancer Center) for reagents. We also thank members of D'Andrea laboratory for valuable input and helpful discussions. H.K. is a recipient of the Leukemia and Lymphoma Society Career Development Fellowship. K.Y is a Harvard University Presidential Scholar. This work was supported by grants RO1DK43889 and RO1HL52725 to A.D.D.

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Authors and Affiliations

  1. Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Hyungjin Kim, Kailin Yang, Donniphat Dejsuphong & Alan D D'Andrea

  2. Leder Human Biology Program, Biological and Biomedical Sciences Program, Harvard Medical School, Boston, Massachusetts, USA

    Kailin Yang

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Contributions

H.K. and A.D.D. designed and interpreted experiments. H.K. and D.D. conducted experiments. K.Y. carried out bioinformatics analysis. H.K. and A.D.D. wrote the manuscript. A.D.D. directed the project.

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Correspondence to Alan D D'Andrea.

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Kim, H., Yang, K., Dejsuphong, D. et al. Regulation of Rev1 by the Fanconi anemia core complex. Nat Struct Mol Biol 19, 164–170 (2012). https://doi.org/10.1038/nsmb.2222

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