# Genetics of HSV DNA Replication

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $824,140

## Abstract

HSV-1, one of nine human herpesviruses (HHVs),
has infected more than 3.7 billion people under the age of
50 (67% of the world’s population) and
is associated with recurrent cold sores, genital lesions, keratitis, corneal
blindness, encephalitis and disseminated neonatal infections. The ability of herpesviruses to establish latent
infections that undergo periodic reactivation significantly contributes to their ability to cause life-long disease,
viral shedding and transmission to new hosts, underscoring the critical need for a better understanding
of their mechanism of DNA replication. Despite the identification of seven viral proteins necessary for HSV
DNA synthesis and three origins of replication, the current understanding of the mechanism of viral DNA
replication is woefully incomplete. Although it has been known for decades that HSV replicates by concatemer
formation, the mechanism by which concatemers form has yet to be identified. Several lines of evidence suggest
that HSV promotes a unique form of DNA replication that utilizes a recombination-dependent mechanism to
produce concatemers. We have identified a two component HSV recombinase comprised of a 5’ to 3’
exonuclease (UL12) and a ssDNA annealing protein or SSAP (ICP8) (exo/SSAP). This complex is reminiscent
of the λ phage Red α/β recombinase required for recombination dependent replication in λ phage and in vivo
recombination-mediated genetic engineering (recombineering). Interestingly exo/SSAP recombinases are
conserved in most dsDNA viruses of bacteria, protozoa, plants and mammals that replicate by concatemer
formation. HSV DNA replication is further complicated by the fact that the viral genome contains nicks and gaps,
and the introduction this damaged genome is known to activate cellular DNA damage response (DDR) pathways,
some of which are antiviral. Thus, HSV has two major challenges: to produce concatemers that can be
packaged while at the same time avoiding cellular antiviral processes.
ICP8 is a central player in all stages of the DNA replication process, acting as a hub for protein-protein
interactions necessary to initiate viral DNA synthesis, bind cooperatively to ssDNA and promote single
strand annealing. In Aim 1 we will explore ICP8 interactions required for initiation of DNA replication and
cooperative binding to ssDNA. In Aim 2 we will explore the role of ICP8 and UL12 in annealing and
recombination-dependent DNA replication. We have shown that the annealing activity of ICP8 is essential for
viral DNA replication during infection, supporting the notion that HSV-1 uses recombination-dependent
mechanisms during DNA replication. In Aim 3 we will examine the role of UL12 in the manipulation of host DDR
pathways. Herpesviruses have evolved an unusual strategy to replicate their genomes that is distinct from
bacterial and cellular DNA replication mechanisms. However, the remarkable degree of conservation between
viruses that replicate through concatemers underscores the fa...

## Key facts

- **NIH application ID:** 9997350
- **Project number:** 2R01AI021747-34A1
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** SANDRA K WELLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $824,140
- **Award type:** 2
- **Project period:** 1984-12-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997350

## Citation

> US National Institutes of Health, RePORTER application 9997350, Genetics of HSV DNA Replication (2R01AI021747-34A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9997350. Licensed CC0.

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