DNA Damage Stress Control Is a Truncated Large T Antigen and Euchromatic Histone Lysine Methyltransferase 2-Dependent...

Area of Science:

• Oncology
• Virology
• Molecular Biology

Background:

• Merkel cell carcinoma (MCC) is an aggressive skin cancer with high mortality.
• Merkel cell polyomavirus (MCPyV) is implicated in 80% of MCC cases, driven by viral oncogenes.
• MCPyV T antigens disrupt cell cycle checkpoints and alter host epigenetics.

Purpose of the Study:

• To investigate the role of MCPyV T antigens in regulating DNA damage response (DDR) in MCC.
• To identify novel interactions between viral T antigens and host cell proteins involved in DDR.
• To explore the therapeutic potential of targeting T antigen-host interactions.

Main Methods:

• Whole-proteome analysis and proximal interactomics were employed.
• T antigen knockdown and EHMT2 inhibition were performed in MCC cells.
• Analysis of DNA damage markers (e.g., γH2Ax) and cell proliferation assays were conducted.

Main Results:

• A novel interaction between MCPyV truncated large T (tLT) antigen and EHMT2 was identified.
• T antigen knockdown decreased DDR protein levels and increased DNA damage.
• EHMT2 inhibition rescued proliferation in T antigen-depleted MCC cells, indicating impaired DDR.
• Combined tLT and EHMT2 inhibition resulted in significant DDR alterations.

Conclusions:

• MCPyV tLT antigen hijacks host DDR machinery, including EHMT2, to promote DNA damage tolerance.
• This hijacking contributes to the genetic stability observed in MCC.
• Targeting the tLT-EHMT2 interaction may represent a novel therapeutic strategy for MCC.