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FAM72A promotes mutagenic repair during antibody maturation

ABSTRACT: FAM72A promotes mutagenic repair during antibody maturation

PROVIDER: PRJNA761718 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15815316.fastq.gz	Fastqsanger.gz
	SRR15815317.fastq.gz	Fastqsanger.gz
	SRR15815318.fastq.gz	Fastqsanger.gz
	SRR15815319.fastq.gz	Fastqsanger.gz
	SRR15815320.fastq.gz	Fastqsanger.gz

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FAM72A promotes mutagenic repair during antibody maturation

Project description:Genome-wide CRISPR screen in murine CH12F3-2 cell line to identify novel factors involved in antibody class switch recombination. FAM72A, a protein with no ascribed function, was identified in this screen as a major determinant during mutagenic uracil repair by antagonizing base excision repair protein UNG2.

2021-09-11 | GSE183706 | GEO

FAM72A antagonizes UNG2 to promote mutagenic repair during antibody maturation.

Project description:Activation-induced cytidine deaminase (AID) catalyses the deamination of deoxycytidines to deoxyuracils within immunoglobulin genes to induce somatic hypermutation and class-switch recombination1,2. AID-generated deoxyuracils are recognized and processed by subverted base-excision and mismatch repair pathways that ensure a mutagenic outcome in B cells3-6. However, why these DNA repair pathways do not accurately repair AID-induced lesions remains unknown. Here, using a genome-wide CRISPR screen, we show that FAM72A is a major determinant for the error-prone processing of deoxyuracils. Fam72a-deficient CH12F3-2 B cells and primary B cells from Fam72a-/- mice exhibit reduced class-switch recombination and somatic hypermutation frequencies at immunoglobulin and Bcl6 genes, and reduced genome-wide deoxyuracils. The somatic hypermutation spectrum in B cells from Fam72a-/- mice is opposite to that observed in mice deficient in uracil DNA glycosylase 2 (UNG2)7, which suggests that UNG2 is hyperactive in FAM72A-deficient cells. Indeed, FAM72A binds to UNG2, resulting in reduced levels of UNG2 protein in the G1 phase of the cell cycle, coinciding with peak AID activity. FAM72A therefore causes U·G mispairs to persist into S phase, leading to error-prone processing by mismatch repair. By disabling the DNA repair pathways that normally efficiently remove deoxyuracils from DNA, FAM72A enables AID to exert its full effects on antibody maturation. This work has implications in cancer, as the overexpression of FAM72A that is observed in many cancers8 could promote mutagenesis.

| S-EPMC9425297 | biostudies-literature

Regulated somatic hypermutation enhances antibody affinity maturation

Project description:Regulated somatic hypermutation enhances antibody affinity maturation

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

Project description: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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