FANCI: from genome guardian to translational therapeutic target

Fanconi anemia complement group I (FANCI), a core component of the Fanconi anemia pathway, has emerged as a potential oncogenic factor across multiple cancer types. Located on chromosome 15q26.1, FANCI encodes a protein named FANCI that forms a stable heterodimer with FANCD2, playing a central role in the DNA damage response and repair. Beyond its involvement in DNA repair, FANCI participates in ribosome biogenesis, meiosis, and mRNA export, underscoring its essential role in maintaining genomic stability. Although FANCI deficiency has traditionally been associated with Fanconi anemia, recent studies have demonstrated that FANCI is overexpressed in various malignancies, where it promotes tumor progression and correlates with poor prognosis. The expression and activity of FANCI are tightly regulated at multiple levels, including transcriptional and post-transcriptional regulation by transcription factors and non-coding RNAs, as well as post-translational modifications such as phosphorylation mediated by PP2A and ATR, monoubiquitination catalyzed by the FANCL-UBE2T complex, and deubiquitination by USP1-UAF1. This review summarizes the functional mechanisms of FANCI across diverse physiological and pathological processes, highlighting its role as a crucial molecular bridge linking genomic stability maintenance to cancer development, and emphasizing its potential as a promising therapeutic target in cancer.