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

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, Mohammad A. Kashem, Derek F. Ceccarelli, Stephen Orlicky, Yifei Fang, Huihui Kuang, Mohammad Mazhab-Jafari, Rossanna C. Pezo, Ashok S. Bhagwat, Trevor J. Pugh, Anne-Claude Gingras, Frank Sicheri () and Alberto Martin ()
Additional contact information
Philip Barbulescu: University of Toronto
Chetan K. Chana: University of Toronto
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
Rukshana Mohamad-Ramshan: Wayne State University
Laura C. McGary: University of Toronto
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
Frank Sicheri: University of Toronto
Alberto Martin: University of Toronto

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52009-x

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