BK Polyomavirus Activates the DNA Damage Response To Prolong S Phase

Area of Science:

• Virology
• Molecular Biology
• Cell Biology

Background:

• BK polyomavirus (PyV) reactivation causes kidney failure in transplant recipients, with current treatment (reduced immunosuppression) risking graft rejection.
• BKPyV infection activates the DNA damage response (DDR) pathways (ATR and ATM), but the mechanism and benefit to viral production remain unclear.
• Understanding the DDR's role in BKPyV infection is crucial for developing targeted therapies.

Purpose of the Study:

• To elucidate why BKPyV activates the DDR via ATR and ATM pathways.
• To understand how this DDR activation prevents DNA damage and enhances viral production.
• To explore the potential of DDR inhibitors as targeted therapies against BKPyV.

Main Methods:

• Primary kidney cells were infected with BKPyV.
• ATR and ATM pathways were inhibited using specific inhibitors.
• Cell cycle progression, DNA damage, and viral production were analyzed.

Main Results:

• ATR inhibition in BKPyV-infected cells led to severe DNA damage and premature mitosis due to aberrant Cdk1 activation.
• ATM was essential for S phase entry and preventing premature mitotic entry post-G2 phase.
• Synergistic activation of ATR and ATM by BKPyV maintains S phase, promoting viral replication and preventing host DNA damage.

Conclusions:

• BKPyV activates the DDR to maintain infected cells in S phase, optimizing viral DNA replication.
• Disrupting this DDR-mediated cell cycle arrest in infected cells leads to catastrophic DNA damage.
• DDR inhibitors show potential for specifically targeting BKPyV-infected cells without harming uninfected cells.