FANCI is an essential component of the Fanconi anemia (FA) pathway responsible for DNA repair and genomic stability maintenance. Primary Function: FANCI functions as part of the FANCI-FANCD2 complex, a sliding DNA clamp that surveys double-stranded DNA and recognizes DNA damage sites by stalling at single-stranded-double-stranded DNA junctions characteristic of stalled replication forks 1. Mechanism: FANCI undergoes monoubiquitination by the FA core complex E3 ligase, facilitated by UBE2T, which transforms the FANCI-FANCD2 complex into its active form 23. This activated complex recruits DNA repair proteins for interstrand crosslink (ICL) repair and participates in replication fork protection 1. FANCI also links DNA damage response to R-loop regulation through interaction with the splicing factor SRSF1, promoting mRNA export and suppressing pathogenic R-loop accumulation 4. Disease Relevance: FANCI mutations cause Fanconi anemia, characterized by bone marrow failure and cancer susceptibility 2. FANCI deficiency leads to R-loop accumulation, genomic instability, and altered tumor progression pathways 5. Paradoxically, FA pathway activation can drive chr15 and extrachromosomal DNA formation, conferring acquired resistance to anticancer therapies 6. Clinical Significance: Understanding FANCI-mediated DNA repair mechanisms and R-loop regulation may inform therapeutic strategies targeting both FA-deficient cancers and FA-pathway-driven drug resistance.