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Structural basis of FANCD2 deubiquitination by USP1-UAF1.

Rennie ML, Arkinson C, Chaugule VK, Toth R, Walden H
Nat Struct Mol Biol 28 356-364 (2021)
Related entries: 7ay0, 7ay2

Cited: 11 times
EuropePMC logo PMID: 33795880

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.

Articles - 7ay1 mentioned but not cited (2)

  1. Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site. Rennie ML, Arkinson C, Chaugule VK, Walden H. Sci Adv 8 eabq6353 (2022)
  2. Ubiquitin-specific protease 11 structure in complex with an engineered substrate mimetic reveals a molecular feature for deubiquitination selectivity. Maurer SK, Mayer MP, Ward SJ, Boudjema S, Halawa M, Zhang J, Caulton SG, Emsley J, Dreveny I. J Biol Chem 299 105300 (2023)


Reviews citing this publication (3)

  1. Deubiquitinases in cancer. Dewson G, Eichhorn PJA, Komander D. Nat Rev Cancer 23 842-862 (2023)
  2. Deubiquitination complex platform: A plausible mechanism for regulating the substrate specificity of deubiquitinating enzymes. Fang YZ, Jiang L, He Q, Cao J, Yang B. Acta Pharm Sin B 13 2955-2962 (2023)
  3. Tools for Decoding Ubiquitin Signaling in DNA Repair. Foster B, Attwood M, Gibbs-Seymour I. Front Cell Dev Biol 9 760226 (2021)

Articles citing this publication (6)

  1. Identification and classification of papain-like cysteine proteinases. Ozhelvaci F, Steczkiewicz K. J Biol Chem 299 104801 (2023)
  2. Structural and biochemical basis of interdependent FANCI-FANCD2 ubiquitination. Lemonidis K, Rennie ML, Arkinson C, Chaugule VK, Clarke M, Streetley J, Walden H. EMBO J 42 e111898 (2023)
  3. The DNA-damage kinase ATR activates the FANCD2-FANCI clamp by priming it for ubiquitination. Sijacki T, Alcón P, Chen ZA, McLaughlin SH, Shakeel S, Rappsilber J, Passmore LA. Nat Struct Mol Biol 29 881-890 (2022)
  4. USP27X variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms. Koch I, Slovik M, Zhang Y, Liu B, Rennie M, Konz E, Cogne B, Daana M, Davids L, Diets IJ, Gold NB, Holtz AM, Isidor B, Mor-Shaked H, Neira Fresneda J, Niederhoffer KY, Nizon M, Pfundt R, Simon M, Stegmann A, Guillen Sacoto MJ, Wevers M, Barakat TS, Yanovsky-Dagan S, Atanassov BS, Toth R, Gao C, Bustos F, Harel T. Life Sci Alliance 7 e202302258 (2024)
  5. Interaction of TAGLN and USP1 promotes ZEB1 ubiquitination degradation in UV-induced skin photoaging. Li Y, Huang X, Jin J, Zhang H, Yang K, Han J, Lv Y, Sun Y, Yao C, Lin T, Zhu C, Liu H. Cell Biosci 13 80 (2023)
  6. USP1-trapping lesions as a source of DNA replication stress and genomic instability. Coleman KE, Yin Y, Lui SKL, Keegan S, Fenyo D, Smith DJ, Rothenberg E, Huang TT. Nat Commun 13 1740 (2022)


Related citations provided by authors (1)

  1. Structural basis of FANCD2 deubiquitination by USP1-UAF1. Rennie ML, Arkinson C, Chaugule VK, Toth R, Walden H Biorxiv - (2020)

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