Unveiling the Function of Fanconi Anemia Complementation Group A Protein (FANCA)

Fanconi anemia is a rare autosomal recessive or X-linked genetic disease characterized by progressive bone marrow failure, various developmental anomalies, and cancer predisposition. Fanconi anemia complementation group A gene is one of the 16 disease-causing genes and has been found to be mutated in more than 60% of Fanconi anemia patients. Using purified proteins, we unveil that FANCA has intrinsic affinity for nucleic acids with preference for singlestrand forms and its nucleic acids binding domain is primarily located at its Cterminus. FANCA binds to RNA with an intriguingly higher affinity than its DNA counterpart. By testing the affinity between FANCA and a variety of DNA structures, we demonstrate that a 5’-flap on DNA facilitates its interaction with FANCA. We also show that FANCA stimulates the endonuclease activity of flap endonuclease 1, an important nuclease to process RNA primers during Okazaki fragment maturation, by the incision of both DNA and RNA flaps. In addition, our preliminary results indicate that deficiency of FANCA causes accumulation of late S phase cells after MMC treatment and results in insufficient activation of ATM and ATR pathways of DNA damage response