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DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells

Andrea Cuconati1, Chandreyee Mukherjee, Denise Perez

  • 1Howard Hughes Medical Institute, Cancer Institute of New Jersey, Rutgers University, Piscataway, New Jersey 08854, USA.

Genes & Development
|November 25, 2003
PubMed

Insights

Adenovirus E1A protein triggers apoptosis by downregulating Myeloid Cell Leukemia 1 (MCL-1), a protein that inhibits BAK. Loss of MCL-1 allows BAK to initiate programmed cell death in infected cells.

Area of Science:

  • Cell Biology
  • Virology
  • Molecular Biology

Background:

  • Adenovirus E1A protein deregulates cell proliferation, promoting viral DNA replication and apoptosis.
  • Apoptosis in infected cells is primarily signaled through the proapoptotic protein BAK.
  • In uninfected cells, BAK is complexed with the anti-apoptotic BCL-2 family member Myeloid Cell Leukemia 1 (MCL-1).

Purpose of the Study:

  • To investigate the role of MCL-1 in adenovirus-induced apoptosis.
  • To elucidate the mechanism by which E1A expression affects MCL-1 and BAK interactions.
  • To determine if MCL-1 down-regulation is a prerequisite for initiating the apoptotic pathway during adenovirus infection.

Main Methods:

  • Analyzing protein-protein interactions between BAK, MCL-1, BAX, and E1B 19K during adenovirus infection.
  • Quantifying MCL-1 protein and mRNA levels in infected versus uninfected cells.
  • Assessing the impact of MCL-1 restoration on E1A-induced apoptosis.
  • Detecting markers of DNA damage, such as phosphorylated H2AX and ATM, in infected cells.

Main Results:

  • E1A expression during adenovirus infection specifically down-regulates MCL-1 by destabilizing the protein and reducing its mRNA levels.
  • Loss of the MCL-1-BAK complex leads to BAK interaction with BAX (in E1B mutant infections) or E1B 19K (in wild-type infections).
  • Restoration of MCL-1 expression rescues infected cells from E1A-induced apoptosis, indicating MCL-1 loss is required for apoptosis initiation.
  • Adenovirus infection induces DNA double-strand breaks, evidenced by accumulated phosphorylated H2AX and ATM, and this DNA damage response also down-regulates MCL-1.

Conclusions:

  • MCL-1 maintains BAK in an inactive state, preventing apoptosis.
  • Adenovirus infection, through E1A expression and induction of DNA damage, leads to MCL-1 down-regulation.
  • The loss of MCL-1 is a critical step required to activate the BAK-mediated apoptotic pathway in response to viral infection and replication stress.

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