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Adenovirus E4 34k and E1b 55k oncoproteins target host DNA ligase IV for proteasomal degradation

Amy Baker1, Kent J Rohleder, Les A Hanakahi

  • 1W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA.

Journal of Virology
|April 27, 2007
PubMed

Insights

Adenovirus infection degrades DNA ligase IV, a key enzyme in nonhomologous end joining (NHEJ). This viral strategy prevents viral genome concatenation and inhibits host DNA repair mechanisms.

Area of Science:

  • Molecular Biology
  • Virology
  • DNA Repair

Background:

  • Adenovirus infection leads to the accumulation of viral genome concatemers formed by nonhomologous end joining (NHEJ).
  • Adenovirus E4orf3 and E4orf6/E1b 55k proteins can prevent this concatenation by targeting the host protein Mre11.
  • The E4orf6/E1b 55k complex inhibits NHEJ independently of Mre11 inactivation.

Purpose of the Study:

  • To investigate the mechanism by which adenovirus inhibits nonhomologous end joining (NHEJ).
  • To determine if other NHEJ components are targeted during adenovirus infection.
  • To elucidate the role of the E4orf6/E1b 55k complex in NHEJ inhibition.

Main Methods:

  • Analysis of DNA ligase IV levels in adenovirus-infected cells.
  • Investigation of the dependence of DNA ligase IV degradation on viral proteins (E4 34k, E1b 55k), proteasomes, and cullin 5.
  • Co-immunoprecipitation assays to detect physical interactions between DNA ligase IV and E1b 55k.

Main Results:

  • Adenovirus infection causes the degradation of DNA ligase IV, an essential enzyme for NHEJ.
  • This degradation is dependent on viral E4 34k and E1b 55k proteins, functional proteasomes, and cellular cullin 5.
  • DNA ligase IV physically interacts with the viral E1b 55k protein, indicating it is a substrate for the adenovirus-specific E3 ubiquitin ligase.

Conclusions:

  • Adenovirus utilizes a specific E3 ubiquitin ligase, involving E4 34k, E1b 55k, and cullin 5, to degrade DNA ligase IV.
  • This degradation represents an additional mechanism by which adenoviruses prevent viral genome concatenation.
  • The targeting of DNA ligase IV contributes to the broader inhibition of host DNA repair pathways by adenoviruses.

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