Genetic inactivation of FAAP100 causes Fanconi anemia due to disruption of the monoubiquitin ligase core complex

Julia Kuehl; Yutong Xue; Fenghua Yuan; Ramanagouda Ramanagoudr-Bhojappa; Simone Pickel; Reinhard Kalb; Settara C. Chandrasekharappa; Weidong Wang; Yanbin Zhang; Detlev Schindler

doi:10.1172/JCI187323

Published April 15, 2025 - More info

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Abstract

The Fanconi anemia (FA)/BRCA DNA repair network promotes the removal of DNA interstrand crosslinks (ICLs) to counteract their devastating consequences, including oncogenesis. Network signaling is initiated by the FA core complex, which consists of seven authentic FA proteins and an FA-associated protein, FAAP100, with incompletely characterized roles and unknown disease associations. Upon activation, the FA core complex functions as a multiprotein E3 ubiquitin ligase centered on its catalytic module, the FANCB-FANCL-FAAP100 (BLP100) subcomplex, for FANCD2 and FANCI monoubiquitylation. Here, we identified a homozygous variant in FAAP100, c.1642A>C, predicting p.(T542P), in a fetus with malformations suggestive of FA. The mutation causes sensitivity to ICL-inducing agents in cells from the affected individual and genetically engineered, FAAP100-inactivated human, avian, zebrafish, and mouse cells. All FAAP100-deficient cell types were rescued by ectopic expression of wild-type FAAP100, but not FAAP100^T542P. In a confirmatory animal model, customized Faap100^–/– mice exhibit embryonic lethality, microsomia, malformations, and gonadal atrophy resembling mice with established FA subtypes. Mechanistically, FAAP100^T542P impairs ligase activity by preventing BLP100 subcomplex formation, resulting in defective FAAP100^T542P nuclear translocation and chromatin recruitment. FAAP100 dysfunction that disrupts the FA pathway and impairs genomic maintenance, together with FAconsistent human manifestations, recommends FAAP100 as a legitimate FA gene, FANCX.

Genetic inactivation of FAAP100 causes Fanconi anemia due to disruption of the monoubiquitin ligase core complex

Julia Kuehl,¹ Yutong Xue,² Fenghua Yuan,³ Ramanagouda Ramanagoudr-Bhojappa,⁴ Simone Pickel,¹ Reinhard Kalb,¹ Settara C. Chandrasekharappa,⁴ Weidong Wang,² Yanbin Zhang,³ and Detlev Schindler¹

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Genetic inactivation of FAAP100 causes Fanconi anemia due to disruption of the monoubiquitin ligase core complex

Julia Kuehl,1 Yutong Xue,2 Fenghua Yuan,3 Ramanagouda Ramanagoudr-Bhojappa,4 Simone Pickel,1 Reinhard Kalb,1 Settara C. Chandrasekharappa,4 Weidong Wang,2 Yanbin Zhang,3 and Detlev Schindler1

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Julia Kuehl,¹ Yutong Xue,² Fenghua Yuan,³ Ramanagouda Ramanagoudr-Bhojappa,⁴ Simone Pickel,¹ Reinhard Kalb,¹ Settara C. Chandrasekharappa,⁴ Weidong Wang,² Yanbin Zhang,³ and Detlev Schindler¹