The critical role of the iron–sulfur cluster and CTC components in DOG-1/BRIP1 function in Caenorhabditis elegans

Abstract FANCJ/BRIP1, initially identified as DOG-1 (Deletions Of G-rich DNA) in Caenorhabditis elegans, plays a critical role in genome integrity by facilitating DNA interstrand cross-link repair and resolving G-quadruplex structures. Its function is tightly linked to a conserved [4Fe–4S] cluster-binding motif, mutations of which contribute to Fanconi anemia and various cancers. This study investigates the critical role of the iron–sulfur (Fe–S) cluster in DOG-1 and its relationship with the cytosolic iron–sulfur protein assembly targeting complex (CTC). We found that a DOG-1 mutant, expected to be defective in Fe–S cluster binding, is primarily localized in the cytoplasm, leading to heightened DNA damage sensitivity and G-rich DNA deletions. We further discovered that the deletion of mms-19, a nonessential CTC component, also resulted in DOG-1 sequestered in cytoplasm and increased DNA damage sensitivity. Additionally, we identified that CIAO-1 and CIAO-2B are vital for DOG-1’s stability and repair functions but unlike MMS-19 have essential roles in C. elegans. These findings confirm the CTC and Fe–S cluster as key elements in regulating DOG-1, crucial for genome integrity. Additionally, this study advances our understanding of the CTC’s role in Fe–S protein regulation and development in C. elegans, offering a model to study its impact on multicellular organism development.