DIFFERENTIAL DISRUPTION OF GENOMIC INTEGRITY AND CELL-CYCLE REGULATION IN NORMAL HUMAN FIBROBLASTS BY THE HPV ONCOPROTEINS

Genomic integrity is maintained by a network of cellular activities th at assess the status of the genome at a given point in time, provide s ignals to proceed with or halt cell cycle progression, and provide for repair of damaged DNA. Mutations in any part of these pathways can ha ve the ultimate effect of disturbing chromosomal integrity. Recent wor k suggests that p53 performs this integrator function in mammalian cel ls. Our present study demonstrates that in mortal cells the expression of E6 and E7 viral oncoproteins of type 16 human papillomavirus each disrupts the integration of these signals by diverged pathways. Cells expressing E6 protein, which binds and degrades the p53 protein, exhib ited alterations in cell cycle control when placed in drug and display ed the ability to amplify the CAD gene. The expression of E7, which bi nds different cellular proteins important for transformation, includin g Rb, led to a p53-independent alteration in cell cycle control, a wid espread cytocidal response, and polyploidy as a mechanism of drug resi stance. These results demonstrate that diverse perturbations of molecu lar pathways can have different effects on chromosomal integrity.