Modularized Functions of the Fanconi Anemia Core Complex

The Fanconi anemia (FA) core complex provides the essential E3 ligase function for spatially defined FANCD2 ubiquitination and FA pathway activation. Of the seven FA gene products forming the core complex, FANCL possesses a RING domain with demonstrated E3 ligase activity. The other six components do not have clearly defined roles. Through epistasis analyses, we identify three functional modules in the FA core complex: a catalytic module consisting of FANCL, FANCB, and FAAP100 is absolutely required for the E3 ligase function, and the FANCA-FANCG-FAAP20 and the FANCC-FANCE-FANCF modules provide nonredundant and ancillary functions that help the catalytic module bind chromatin or sites of DNA damage. Disruption of the catalytic module causes complete loss of the core complex function, whereas loss of any ancillary module component does not. Our work reveals the roles of several FA gene products with previously undefined functions and a modularized assembly of the FA core complex. [Display omitted] •FA gene products that form the E3 ligase catalytic core module are identified•FANCG/FANCF-containing modules mediate DNA damage recruitment of the catalytic module•A model of modularized functional assembly of the FA core complex is proposed Huang et al. identify three functional modules in the Fanconi anemia (FA) core complex. The FANCL-FANCB-FAAP100 catalytic module is essential for the E3 ligase function, disruption of which leads to total loss of the core complex function. The FANCA-FANCG-FAAP20 and FANCC-FANCE-FANCF modules provide nonredundant and ancillary functions supporting the chromatin/DNA damage association of the catalytic module. The modularized assembly of the FA core complex reveals that FA core genes have diverse functions in activating the FA pathway.