Picture of Linda Chelico

Linda Chelico Professor Biochemistry, Microbiology & Immunology

6B63, Health Sciences

Research Area(s)

  • HIV restriction factors, DNA deaminases, Mutagenesis, Enzyme mechanisms


Areas of Expertise

HIV restriction factors, DNA deaminases, mutagenesis, enzyme mechanisms

In the News



Research Interests

Our lab has two main projects that examine host restriction factors that restrict viral replication and the origins of mutations in cancer cells. These seemingly disparate topics are unified by the enzyme family involved in both processes, the APOBEC3 family of cytosine deaminases.

Retrotransposons and endogenous retroviruses have been genomic parasites in organisms throughout evolution and have contributed to both species evolution and disease. The APOBEC (Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide) family of enzymes present in their earliest form acted as a defense to retroelements. Due to expansion of retroelements through evolution there was a corresponding expansion in the APOBEC family. The most recent expansion in placental mammals formed the APOBEC-like 3 (APOBEC3) family in response to ancient pathogenic retroviruses. Humans contain seven APOBEC3 (A3) enzymes (A3A, A3B, A3C, A3D, A3F, A3G, and A3H).

The A3 enzymes act as host restriction factors to inhibit retroelement, e.g., LINE-1, retrovirus, e.g., HIV-1,  DNA virus, e.g., EBV, or RNA virus, e.g., coronavirus, replication through either nucleic acid binding ability or activity as single-stranded (ss) DNA and RNA cytosine deaminases that catalyze the formation of promutagenic uracils. Our lab studies from a biochemical and cellular perspective how A3 enzymes restrict the replication of the retrovirus HIV-1.

Restriction of the replication of HIV-1 by A3 enzymes occurs through the ssDNA cytosine deamination activity of A3 enzymes which results in hypermutated and inactivated viral genomes (Figure 1). HIV-1 can suppress A3 restriction factors by encoding the accessory protein Vif that hijacks the host ubiquitination system to induce polyubiquitination and proteasomal degradation of A3 enzymes.

Our lab studies:

(1) The biochemistry of A3 enzymes and how A3 enzymes interact with each other and cellular and viral proteins to restrict viral replication.

(2) The biochemical interface of HIV-1 Vif and A3 enzymes and the determinants of Vif-mediated degradation of A3 enzymes.

Despite these benefits of A3 enzymes for suppression of retroelements and viruses, there is evidence that there is a cost to this defense system in the form of A3-catalyzed deaminations that occur in our genomes during our lifetime. Usually, redundant DNA repair mechanisms can remove uracils and negate most of these promutagenic lesions. However, with the development of Next Generation Sequencing technology to obtain greater sequencing depth, it is clear that many cancer genomes have a bias of A3-induced mutations at cytosines and most cancer cells or tumors show overexpression of A3A, A3B, or A3H mRNA, suggesting that some uracils persist and develop into mutations.

Our lab studies:

(1)  The mechanisms by which A3 enzymes gain access to transiently single-stranded DNA in the genome and compete with other single-stranded DNA binding proteins, such as replication protein A (RPA).

(2)  The influence of A3-induced mutations on the fate of tumor cells and non-tumorigenic epithelial cells using mouse xenograft models.

(3) How interactions of A3 enzymes with other cellular proteins influence genomic stability and tumorigenesis.

Recent Publications