Biology subjects

Barbulescu, P.

Publications and source records attributed to Barbulescu, P..

2 recordsLinked to original sources

bioRxiv2026

Oncogenic E3-ligase adaptors MAGE-A3/6 promote cancer cell migration via BAP18 degradation

Cancer testis antigens are widely expressed in human malignancies. Melanoma-Associated Antigens (MAGE) A3 and A6 have been proposed to modulate protein turnover and metabolism in cancer cells. However, the substrate specificity of MAGE-A3/6 and the impact on cancer cell behavior remain poorly understood. Although previous research has identified binding partners, a molecularly validated target for MAGE-A3/6-mediated proteasomal degradation has not been described. In this study, we redefine the substrate specificity of MAGE-A3/6 and present a mechanistic framework for substrate binding, polyubiquitination, and subsequent degradation. We identify BPTF-Associated Protein of 18kDa (BAP18) as a bona fide novel substrate of MAGE-A3/6 and demonstrate its direct regulation via a molecularly defined substrate-degron-E3-adaptor interaction. The degradation of BAP18 by MAGE-A3/6 underlies phenotypic alterations in cancer cells, such as enhanced migratory capacity. This previously unrecognized molecular link is observed in both cancer cell lines and human cancer tissues, supporting a role as a fundamental oncogenic process. The discovery of a molecularly defined interaction between MAGE-A3/6 and their substrate enables systematic investigation into oncogenic protein degradation in human cancers and may inform future therapeutic strategies that leverage the molecular function of aberrantly reexpressed germline proteins in cancer.

cancer biology↗

bioRxiv2020

FAM72A antagonizes UNG2 to promote mutagenic uracil repair during antibody maturation

Activation-induced cytidine deaminase (AID) catalyzes the deamination of deoxycytidines within Immunoglobulin (Ig) genes to induce somatic hypermutation (SHM) and class switch recombination (CSR) 1,2. AID-induced deoxyuracils within Ig loci are recognized and processed by subverted base excision and mismatch repair pathways that ensure a mutagenic outcome in B lymphocytes 3-8. However, it is unclear why DNA repair pathways that remove deoxyuracil from DNA are not efficient at faithfully repairing AID-induced lesions. Here, we identified through a genome-wide CRISPR screen that FAM72A, a protein with no ascribed function, is a major determinant for the error-prone processing of deoxyuracil. Fam72a-deficient CH12F3-2 B cells and primary B cells from Fam72a-/- mice have reduced CSR and SHM frequencies. The SHM spectrum in B cells from Fam72a-/- mice is opposite to that observed in Ung2-/- mice 9, suggesting that UNG2 is hyperactive in FAM72A-deficient cells. Indeed, FAM72A binds to UNG2 resulting in reduced UNG2 activity, and significantly reduced protein levels in the G1 phase, coinciding with peak AID activity. This effect leads to increased genome-wide deoxyuracils in B cells. By antagonizing UNG2, FAM72A therefore increases U*G mispairs that engage mutagenic mismatch repair promoting error-prone processing of AID-induced deoxyuracils. This work shows that FAM72A bridges base-excision repair and mismatch repair to modulate antibody maturation.

immunology↗