APOBEC: A molecular driver in cervical cancer pathogenesis

Abstract

Cervical cancer is one of the foremost common cancers in women. Human papillomavirus (HPV) infection remains a major risk factor of cervical cancer. In addition, numerous other genetic and epigenetic factors also are involved in the underlying pathogenesis of cervical cancer. Recently, it has been reported that apolipoprotein B mRNA editing enzyme catalytic polypeptide like (APOBEC), DNA-editing protein plays an important role in the molecular pathogenesis of cancer. Particularly, the APOBEC3 family was shown to induce tumor mutations by aberrant DNA editing mechanism. In general, APOBEC3 enzymes play a pivotal role in the deamination of cytidine to uridine in DNA and RNA to control diverse biological processes such as regulation of protein expression, innate immunity, and embryonic development. Innate antiviral activity of the APOBEC3 family members restrict retroviruses, endogenous retro-element, and DNA viruses including the HPV that is the leading risk factor for cervical cancer. This review briefly describes the pathogenesis of cervical cancer and discusses in detail the recent findings on the role of APOBEC in the molecular pathogenesis of cervical cancer.

Keywords: Cytidine deaminase; DNA/RNA editing; HPV; Mutation; Viral restriction.

Fig. 1

Structural organization of APOBEC family genes The schematic diagram shows the protein structures of the APOBEC family members. The domains and position of the evolutionarily conserved residues are shown. The color-coded in orange is the catalytically inactive CDA domain and green is the catalytically active CDA domain covalently linked on the same peptide in APOBEC3 family members 3B, 3C-E, 3F, and 3G. Their chromosomal localization is mentioned on the right side. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Mechanism of APOBEC-mediated cytosine deamination and APOBEC-induced mutations in the host genome. A) APOBEC-mediated catalytic activity. APOBEC family enzymes catalyze the hydrolytic reaction of cytosine to uracil (C-to-U) and induce DNA degradation or mutations if the APOBEC3-mediated conversion of cytosine to uracil is not repaired. B) Induction of C > T mutation by APOBEC. The illustration shows the C > T mutation resulting from a series of biochemical changes including cytosine deamination and defect in proofreading during replication.

Fig. 3

APOBEC SBS 2 and 13 signature mutations in cervical cancer. A) APOBEC SBS2 signature mutations. SBS2 mutations are generated directly by DNA replication across uracil or by error-prone polymerases replicating across abasic sites generated by base excision repair removal of uracil. TCA context mutations are more prevalent >50% than TCC, TCG, and TCT. B) Distribution of APOBEC SBS2 Signature mutations found in human cancers. APOBEC3 SBS2 signature mutations are more frequently observed in cervical and bladder cancers. C) APOBEC SBS13 signature mutations.SBS13 mutations are generated by error-prone polymerases (such as REV1) replicating across abasic sites generated by base excision repair removal of uracil. TCA and TCT context mutations are more common in SBS13 signature mutation. D) Distribution of APOBEC SBS13 signature mutations in human cancers.SBS13 is usually found in the same samples as SBS2. APOBEC3 SBS13 signature mutations are commonly observed in cervical and bladder cancers. (The figure was generated using COSMIC data base).

Fig. 4

APOBEC3A/3B deletion polymorphism and miRNA-mediated regulation of APOBEC3A, B and APOBEC3A/B fusion transcripts A) Schematic diagram of APOBEC3A/3B deletion polymorphism. Illustration on top shows both APOBEC3A (Green color) and APOBEC3B (Orange color) and 29.6 kb deletion border region marked a blue color box. The diagram in the bottom shows the APOBEC3A/3B fusion transcript. B), C) & D) Diagram shows the 3′-UTR map of miRNAs that modulates the post-transcriptional regulation of APOBEC3A, APOBEC3B, and APOBEC3A/B fusion transcript, respectively. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)