Structural basis of FANCD2 deubiquitination by USP1-UAF1

doi:10.1038/s41594-021-00576-8

. 2021 Apr;28(4):356-364.

doi: 10.1038/s41594-021-00576-8. Epub 2021 Apr 1.

Structural basis of FANCD2 deubiquitination by USP1-UAF1

Martin L Rennie¹, Connor Arkinson^{2

3}, Viduth K Chaugule^{2

3}, Rachel Toth³, Helen Walden^{4

5}

Affiliations

¹ Institute of Molecular Cell and Systems Biology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. Martin.Rennie@glasgow.ac.uk.
² Institute of Molecular Cell and Systems Biology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
³ MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, UK.
⁴ Institute of Molecular Cell and Systems Biology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. Helen.Walden@glasgow.ac.uk.
⁵ MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, UK. Helen.Walden@glasgow.ac.uk.

PMID: 33795880
DOI: 10.1038/s41594-021-00576-8

Free article

Structural basis of FANCD2 deubiquitination by USP1-UAF1

Martin L Rennie et al. Nat Struct Mol Biol. 2021 Apr.

Free article

. 2021 Apr;28(4):356-364.

doi: 10.1038/s41594-021-00576-8. Epub 2021 Apr 1.

Authors

Martin L Rennie¹, Connor Arkinson^{2

3}, Viduth K Chaugule^{2

3}, Rachel Toth³, Helen Walden^{4

5}

Affiliations

¹ Institute of Molecular Cell and Systems Biology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. Martin.Rennie@glasgow.ac.uk.
² Institute of Molecular Cell and Systems Biology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
³ MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, UK.
⁴ Institute of Molecular Cell and Systems Biology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. Helen.Walden@glasgow.ac.uk.
⁵ MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, UK. Helen.Walden@glasgow.ac.uk.

PMID: 33795880
DOI: 10.1038/s41594-021-00576-8

Abstract

Ubiquitin-specific protease 1 (USP1) acts together with the cofactor UAF1 during DNA repair processes to specifically remove monoubiquitin signals. One substrate of the USP1-UAF1 complex is the monoubiquitinated FANCI-FANCD2 heterodimer, which is involved in the repair of DNA interstrand crosslinks via the Fanconi anemia pathway. Here we determine structures of human USP1-UAF1 with and without ubiquitin and bound to monoubiquitinated FANCI-FANCD2. The crystal structures of USP1-UAF1 reveal plasticity in USP1 and key differences to USP12-UAF1 and USP46-UAF1, two related proteases. A cryo-EM reconstruction of USP1-UAF1 in complex with monoubiquitinated FANCI-FANCD2 highlights a highly orchestrated deubiquitination process, with USP1-UAF1 driving conformational changes in the substrate. An extensive interface between UAF1 and FANCI, confirmed by mutagenesis and biochemical assays, provides a molecular explanation for the requirement of both proteins, despite neither being directly involved in catalysis. Overall, our data provide molecular details of USP1-UAF1 regulation and substrate recognition.

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References

1. Yau, R. & Rape, M. The increasing complexity of the ubiquitin code. Nat. Cell Biol. 18, 579–586 (2016). - PubMed - DOI
1. Mevissen, T. E. T. & Komander, D. Mechanisms of deubiquitinase specificity and regulation. Annu. Rev. Biochem. 86, 159–192 (2017). - PubMed - DOI
1. Grabbe, C., Husnjak, K. & Dikic, I. The spatial and temporal organization of ubiquitin networks. Nat. Rev. Mol. Cell Biol. 12, 295–307 (2011). - PubMed - PMC - DOI
1. Nijman, S. M. B. et al. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol. Cell 17, 331–339 (2005). - PubMed - DOI
1. Huang, T. T. et al. Regulation of monoubiquitinated PCNA by DUB autocleavage. Nat. Cell Biol. 8, 339–347 (2006). - PubMed

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[1] Yau, R. & Rape, M. The increasing complexity of the ubiquitin code. Nat. Cell Biol. 18, 579–586 (2016). - PubMed - DOI

[2] Yau, R. & Rape, M. The increasing complexity of the ubiquitin code. Nat. Cell Biol. 18, 579–586 (2016). - PubMed - DOI

[3] Mevissen, T. E. T. & Komander, D. Mechanisms of deubiquitinase specificity and regulation. Annu. Rev. Biochem. 86, 159–192 (2017). - PubMed - DOI

[4] Mevissen, T. E. T. & Komander, D. Mechanisms of deubiquitinase specificity and regulation. Annu. Rev. Biochem. 86, 159–192 (2017). - PubMed - DOI

[5] Grabbe, C., Husnjak, K. & Dikic, I. The spatial and temporal organization of ubiquitin networks. Nat. Rev. Mol. Cell Biol. 12, 295–307 (2011). - PubMed - PMC - DOI

[6] Grabbe, C., Husnjak, K. & Dikic, I. The spatial and temporal organization of ubiquitin networks. Nat. Rev. Mol. Cell Biol. 12, 295–307 (2011). - PubMed - PMC - DOI

[7] Nijman, S. M. B. et al. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol. Cell 17, 331–339 (2005). - PubMed - DOI

[8] Nijman, S. M. B. et al. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol. Cell 17, 331–339 (2005). - PubMed - DOI

[9] Huang, T. T. et al. Regulation of monoubiquitinated PCNA by DUB autocleavage. Nat. Cell Biol. 8, 339–347 (2006). - PubMed

[10] Huang, T. T. et al. Regulation of monoubiquitinated PCNA by DUB autocleavage. Nat. Cell Biol. 8, 339–347 (2006). - PubMed

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Structural basis of FANCD2 deubiquitination by USP1-UAF1

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Structural basis of FANCD2 deubiquitination by USP1-UAF1

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