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FAM72A degrades UNG2 through the GID/CTLH complex to promote mutagenic repair during antibody maturation

Author

Listed:
  • Philip Barbulescu

    (University of Toronto)

  • Chetan K. Chana

    (University of Toronto
    Sinai Health System)

  • Matthew K. Wong

    (University of Toronto)

  • Ines Ben Makhlouf

    (University of Toronto)

  • Jeffrey P. Bruce

    (University of Toronto)

  • Yuqing Feng

    (University of Toronto)

  • Alexander F. A. Keszei

    (University of Toronto)

  • Cassandra Wong

    (University of Toronto
    Wayne State University)

  • Rukshana Mohamad-Ramshan

    (Wayne State University)

  • Laura C. McGary

    (University of Toronto
    Wayne State University)

  • Mohammad A. Kashem

    (University of Toronto)

  • Derek F. Ceccarelli

    (Sinai Health System)

  • Stephen Orlicky

    (Sinai Health System)

  • Yifei Fang

    (University of Toronto)

  • Huihui Kuang

    (New York University School of Medicine)

  • Mohammad Mazhab-Jafari

    (University of Toronto)

  • Rossanna C. Pezo

    (Sunnybrook Health Sciences Center)

  • Ashok S. Bhagwat

    (Wayne State University)

  • Trevor J. Pugh

    (University of Toronto)

  • Anne-Claude Gingras

    (Sinai Health System
    University of Toronto)

  • Frank Sicheri

    (University of Toronto
    Sinai Health System
    University of Toronto)

  • Alberto Martin

    (University of Toronto)

Abstract

A diverse antibody repertoire is essential for humoral immunity. Antibody diversification requires the introduction of deoxyuridine (dU) mutations within immunoglobulin genes to initiate somatic hypermutation (SHM) and class switch recombination (CSR). dUs are normally recognized and excised by the base excision repair (BER) protein uracil-DNA glycosylase 2 (UNG2). However, FAM72A downregulates UNG2 permitting dUs to persist and trigger SHM and CSR. How FAM72A promotes UNG2 degradation is unknown. Here, we show that FAM72A recruits a C-terminal to LisH (CTLH) E3 ligase complex to target UNG2 for proteasomal degradation. Deficiency in CTLH complex components result in elevated UNG2 and reduced SHM and CSR. Cryo-EM structural analysis reveals FAM72A directly binds to MKLN1 within the CTLH complex to recruit and ubiquitinate UNG2. Our study further suggests that FAM72A hijacks the CTLH complex to promote mutagenesis in cancer. These findings show that FAM72A is an E3 ligase substrate adaptor critical for humoral immunity and cancer development.

Suggested Citation

  • Philip Barbulescu & Chetan K. Chana & Matthew K. Wong & Ines Ben Makhlouf & Jeffrey P. Bruce & Yuqing Feng & Alexander F. A. Keszei & Cassandra Wong & Rukshana Mohamad-Ramshan & Laura C. McGary & Moha, 2024. "FAM72A degrades UNG2 through the GID/CTLH complex to promote mutagenic repair during antibody maturation," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52009-x
    DOI: 10.1038/s41467-024-52009-x
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