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

Summary

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.

Graphical abstract

Highlights

• •

  A3B is upregulated after 5-AzaC treatment and related to 5-AzaC sensitivity in HPV+ HNSCC

• •

  Full-length A3B prefers longer substrates and a purine at −2 site biochemically

• •

  A3B also prefers a purine at −2 site in both HPV+ and HPV− HNSCC cells

• •

  A3B signature at -2 site linked to poor patient survival in HPV+ HNSCC low smokers

Abstract

Biological sciences; Biochemistry; Cancer