ArticleNature communications2024
FAM72A degrades UNG2 through the GID/CTLH complex to promote mutagenic repair during antibody maturation.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Multimodal substrate recruitment enables CTLHNature communications · 2026Article
- Article
- Ubiquitylation by the GID/CTLH complex regulates the metabolic and innate immune response of macrophages to infection by Mycobacterium tuberculosis.PLoS pathogens · 2026Article
- Charged molecular glue discovery enabled by targeted degron display.Nature chemical biology · 2026Article
- Article
- Proteome-wide C-degron activity profiling connects conditional regulation of the CTLH E3 ligase complex to ribosome biogenesis.bioRxiv : the preprint server for biology · 2026Article
- Loss of RanBP9 cooperates with p53 deficiency to promote sarcomagenesis.Frontiers in oncology · 2026Article
- The role of chimeric FAM72B transcripts generated by intergenic mRNA trans-splicing in breast cancer.Functional & integrative genomics · 2025Article
- The many faces of the GID/CTLH E3 ligase complex.Biochemical Society transactions · 2025Review
- MKLN1-dependent GID4/CTLH E3 ubiquitin ligase complex assemblies are required to support B-cell antibody diversification.Journal of immunology (Baltimore, Md. : 1950) · 2025Article
- Spotlight onGenes · 2025Article
- The generation and consequences of N-terminal proteoform diversity.Cell reports · 2025Review
- RANBP9 and RANBP10 cooperate in regulating non-small cell lung cancer proliferation.Journal of experimental & clinical cancer research : CR · 2025Article
- FAM72A promotes UNG2 degradation and mutagenesis in human cancer cells.Scientific reports · 2025Article
- mTORC1 regulates the pyrimidine salvage pathway by controlling UCK2 turnover via the CTLH-WDR26 E3 ligase.Cell reports · 2025Article
Corrections and comments
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Authors and funding
22 authors.
Funding
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.
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