Exploring ABOBEC3A and APOBEC3B substrate specificity and their role in HPV positive head and neck cancer

Christina Papini; Zechen Wang; Shalley N Kudalkar; Travis Parke Schrank; Su Tang; Tomoaki Sasaki; Cory Wu; Brandon Tejada; Samantha J Ziegler; Yong Xiong; Natalia Issaeva; Wendell G Yarbrough; Karen S Anderson

doi:10.1016/j.isci.2022.105077

Exploring ABOBEC3A and APOBEC3B substrate specificity and their role in HPV positive head and neck cancer

iScience. 2022 Sep 5;25(10):105077. doi: 10.1016/j.isci.2022.105077. eCollection 2022 Oct 21.

Authors

Affiliations

¹ Department of Pharmacology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520, USA.
² Department of Otolaryngology/Head and Neck Surgery, University of North Carolina, Chapel Hill, NC 27599, USA.
³ Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
⁴ Department of Pathology and Lab Medicine, Lineberger Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.

Abstract

APOBEC3 family members are cytidine deaminases catalyzing conversion of cytidine to uracil. Many studies have established a link between APOBEC3 expression and cancer development and progression, especially APOBEC3A (A3A) and APOBEC3B (A3B). Preclinical studies with human papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) and clinical trial specimens revealed induction of A3B, but not A3A expression after demethylation. We examined the kinetic features of the cytidine deaminase activity for full length A3B and found that longer substrates and a purine at -2 position favored by A3B, whereas A3A prefers shorter substrates and an adenine or thymine at -2 position. The importance and biological significance of A3B catalytic activity rather than A3A and a preference for purine at the -2 position was also established in HPV+ HNSCCs. Our study explored factors influencing formation of A3A and A3B-related cancer mutations that are essential for understanding APOBEC3-related carcinogenesis and facilitating drug discovery.

Keywords: Biochemistry; Biological sciences; Cancer.

Abstract

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