Mouse papillomavirus type 1 (MmuPV1) DNA is frequently integrated in benign tumors by microhomology-mediated end-joining

PLoS Pathog. 2021 Aug 3;17(8):e1009812. doi: 10.1371/journal.ppat.1009812. eCollection 2021 Aug.

Abstract

MmuPV1 is a useful model for studying papillomavirus-induced tumorigenesis. We used RNA-seq to look for chimeric RNAs that map to both MmuPV1 and host genomes. In tumor tissues, a higher proportion of total viral reads were virus-host chimeric junction reads (CJRs) (1.9‰ - 7‰) than in tumor-free tissues (0.6‰ - 1.3‰): most CJRs mapped to the viral E2/E4 region. Although most of the MmuPV1 integration sites were mapped to intergenic regions and introns throughout the mouse genome, integrations were seen more than once in several genes: Malat1, Krt1, Krt10, Fabp5, Pard3, and Grip1; these data were confirmed by rapid amplification of cDNA ends (RACE)-Single Molecule Real-Time (SMRT)-seq or targeted DNA-seq. Microhomology sequences were frequently seen at host-virus DNA junctions. MmuPV1 infection and integration affected the expression of host genes. We found that factors for DNA double-stranded break repair and microhomology-mediated end-joining (MMEJ), such as H2ax, Fen1, DNA polymerase Polθ, Cdk1, and Plk1, exhibited a step-wise increase and Mdc1 a decrease in expression in MmuPV1-infected tissues and MmuPV1 tumors relative to normal tissues. Increased expression of mitotic kinases CDK1 and PLK1 appears to be correlated with CtIP phosphorylation in MmuPV1 tumors, suggesting a role for MMEJ-mediated DNA joining in the MmuPV1 integration events that are associated with MmuPV1-induced progression of tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Animals, Newborn
  • DNA Breaks, Double-Stranded
  • DNA End-Joining Repair*
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism*
  • DNA, Viral / genetics*
  • Female
  • Genome, Viral
  • Homologous Recombination
  • Keratinocytes / metabolism*
  • Keratinocytes / virology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Papilloma / genetics*
  • Papilloma / virology
  • Papillomaviridae / genetics*
  • Papillomavirus Infections / genetics*
  • Papillomavirus Infections / metabolism
  • Papillomavirus Infections / virology
  • RNA-Seq

Substances

  • DNA, Viral
  • DNA Repair Enzymes