Host translesion polymerases are required for viral genome integrity

Sebastian Zeltzer, Pierce Longmire, Marek Svoboda, Giovanni Bosco, Felicia Goodrum

Research output: Contribution to journalArticlepeer-review

Abstract

Human cells encode up to 15 DNA polymerases with specialized functions in chromosomal DNA synthesis and damage repair. In contrast, complex DNA viruses, such as those of the herpesviridae family, encode a single B-family DNA polymerase. This disparity raises the possibility that DNA viruses may rely on host polymerases for synthesis through complex DNA geometries. We tested the importance of error-prone Y-family polymerases involved in translesion synthesis (TLS) to human cytomegalovirus (HCMV) infection. We find most Y-family polymerases involved in the nucleotide insertion and bypass of lesions restrict HCMV genome synthesis and replication. In contrast, other TLS polymerases, such as the polymerase complex, which extends past lesions, was required for optimal genome synthesis and replication. Depletion of either the pol complex or the suite of insertion polymerases demonstrate that TLS polymerases suppress the frequency of viral genome rearrangements, particularly at GC-rich sites and repeat sequences. Moreover, while distinct from HCMV, replication of the related herpes simplex virus type 1 is impacted by host TLS polymerases, suggesting a broader requirement for host polymerases for DNA virus replication. These findings reveal an unexpected role for host DNA polymerases in ensuring viral genome stability.

Original languageEnglish (US)
Article numbere2203203119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number33
DOIs
StatePublished - Aug 16 2022

Keywords

  • DNA repair
  • TLS polymerase
  • cytomegalovirus
  • genome replication
  • herpesvirus

ASJC Scopus subject areas

  • General

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