Integrative proteomics defines FANCA as a multifunctional hub linking DNA repair to translation.

Fanconi anemia (FA) is a genome instability syndrome caused by defects in the FANC/BRCA DNA repair pathway, yet its broad clinical heterogeneity suggests functions beyond DNA repair. Using an integrative interactomics strategy combining endogenous co-immunoprecipitation, proximity-dependent labeling, in silico network integration, and functional analyses, we construct an interaction score-based multilayered FANCA protein-protein interaction landscape. Beyond its association with the FANCcore complex and DNA repair machineries, FANCA engages with proteins involved in chromatin remodeling, RNA metabolism, and ribosome biogenesis. Functional analyses reveal ribosome-related processes as a robust feature of FANCA-associated networks. Quantitative analyses further reveal alterations in ribosome protein stoichiometry, suggesting defective ribosome biogenesis. Our findings suggest translation alterations may explain the pleiotropic clinical manifestations of FA by posing FANCA as a link between genome maintenance, ribosome biogenesis, and translation. Our study highlights how integrative interaction allows deciphering regulatory roles of DNA repair proteins in cellular homeostasis and disease.