A NON-CANONICAL ROLE FOR RUNX PROTEINS IN THE FANCONI ANEMIA PATHWAY OF DNA REPAIR

Abstract

RUNX PROTEINS ARE EVOLUTIONARILY CONSERVED TRANSCRIPTION FACTORS. RUNX PROTEINS HETERODIMERIZE WITH CBF? AND BIND TO RUNX CONSENSUS SITES TO MEDIATE TRANSCRIPTION. THIS STUDY SEEKS TO ELUCIDATE THE ROLE OF RUNX IN TUMORIGENESIS AS RUNX DYSREGULATION IS FREQUENTLY FOUND IN HUMAN MALIGNANCIES. PROTEOMIC ANALYSIS IDENTIFYING RUNX INTERACTORS, FOUND AN ENRICHMENT FOR DNA REPAIR PROTEINS, INCLUDING FANCI. FANCI IS PART OF THE FANCONI ANEMIA PATHWAY THAT REPAIRS DNA INTERSTRAND CROSSLINKS THROUGH THE MONOUBIQUITINATION AND RECRUITMENT OF FANCI AND FANCD2 HETERODIMER TO DNA DAMAGE SITES. CO-IMMUNOPRECIPITATION ASSAY VALIDATED RUNX INTERACTION WITH FANCI AND FANCD2 AND INTERSTRAND CROSSLINKING DRUG FURTHER STIMULATES THE ASSOCIATION. THIS STUDY REVEALS THAT RUNX IS REQUIRED FOR THE RECRUITMENT OF FANCI AND FANCD2. FURTHER ANALYSIS OF THE HUMAN DISEASE MODEL, SHOWS THAT LEUKEMIC RUNX1-ETO DISRUPTS THE FANCONI ANEMIA PATHWAY. BY CONTROLLING DNA REPAIR, WE PROPOSE THAT RUNX DYSREGULATION IS RES