Publication Date

2014-02-06

Availability

Embargoed

Embargo Period

2016-02-06

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Biochemistry and Molecular Biology (Medicine)

Date of Defense

2014-01-28

First Committee Member

Yanbin Zhang

Second Committee Member

Thomas K. Harris

Third Committee Member

Lan Wang

Fourth Committee Member

Priyamvada Rai

Abstract

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.

Keywords

Fanconi anemia; FANCA; Okazaki fragment; ICL

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