Weitzman Lab

We have a particular interest in the interactions between viruses and DNA repair pathways of the host cell. Cells have complex machineries in place to monitor and repair damage to their own genomes, and we have discovered that this cellular machinery also recognizes the foreign viral genome as damaged DNA. Viral infection and replication can result in a cascade of signaling events that lead to checkpoint induction and cell cycle arrest. This can have a deleterious outcome for some viruses, while others can counterattack by dismantling the cellular DNA repair machinery or exploiting aspects of it to aid their own replication. We are interested in the interactions between DNA viruses and the host cell repair machineries. Specifically, we have found that infection with mutant Adenovirus, replicating Adeno-associated virus (AAV) or Herpes Simplex Virus (HSV) induces DNA damage signaling, resulting in multi-faceted outcomes for both virus and host.

Viral infection presents the cell with large amounts of foreign DNA. In the case of Adenovirus infection, the viral genome is protected at the 5’ end with a covalently attached terminal protein. We are currently interested in indentifying cellular proteins that facilitate removal of this terminal protein, thereby enabling end-joining of viral genomes and limiting Adenovirus replication.

We are also interested in recognition of viral genomes by antiviral proteins of the APOBEC family of cytidine deaminases. We have recently discovered that AAV is potently inhibited by APOBEC family members 3A and 3B, in a mechanism separable from the deaminase activity of these proteins. The small genome size and simplicity of AAV makes it an attractive model system to study the deaminase-independent antiviral activity of APOBEC proteins.

During infection, viruses must manipulate the cellular environment to create favorable conditions for their own replication. This often involves targeting restrictive host factors for proteasome-mediated degradation. We are employing tandem mass spectroscopy approaches to identify novel substrates for viral ubiquitin ligases. We are specifically interested in targets of the HSV-1 immediate early protein ICP0 and the E1B55K/E4orf6 complex of Adenovirus.

From the discovery of transformation and splicing to the role of p53, viruses have historically revealed key players in fundamental cellular processes. In addition to studying basic virology, our lab is particularly interested in using viruses to explore basic processes of cell biology. We have used Adenovirus mutants to explore the role of the Mre11 complex in sensing damaged DNA and we are currently using HSV-1 to study the significance of ubiquitination in DNA damage response signaling and transcriptional repression.