Human papillomavirus type 16 E6 and E7 oncogenes abrogate radiation-induced DNA damage responses in vivo through p53-dependent and p53-independent pathways

Area of Science:

• Molecular Biology
• Oncology
• Virology

Background:

• High-risk human papillomaviruses (HPVs) E6 and E7 oncoproteins are known to disrupt cellular functions.
• E6 inhibits p53, and E7 inhibits retinoblastoma protein (pRb), affecting cell cycle control.
• These oncoproteins can abrogate DNA damage-induced growth arrest in cultured cells.

Purpose of the Study:

• To investigate how HPV-16 E6 and E7 oncoproteins modulate DNA damage responses in vivo using transgenic mouse models.
• To determine the specific roles of E6 and E7 in abrogating radiation-induced growth arrest in the epidermis.
• To elucidate the involvement of p53 and pRb pathways in these cellular responses to DNA damage.

Main Methods:

• Utilized transgenic mice expressing HPV-16 E6 or E7 in the epidermis.
• Administered ionizing radiation to assess DNA damage response.
• Analyzed DNA synthesis inhibition, protein levels (p53, p21), and utilized p53-null mice for pathway analysis.

Main Results:

• Both E6 and E7 abrogated inhibition of DNA synthesis in the epidermis post-irradiation.
• E6 suppressed increases in p53 and p21 levels, while E7 did not.
• Radiation-induced epidermal growth arrest involves both p53-dependent and independent pathways, with E6/E7 showing more complete abrogation than p53-null models.

Conclusions:

• E6 and E7 oncoproteins modulate both p53-dependent and p53-independent cellular responses to radiation.
• Conserved regions 1 and 2 of E7 are crucial for modulating DNA damage responses in vivo, linking pRb inactivation to these effects.
• pRb and/or pRb-like proteins likely mediate cellular responses to radiation through both p53-dependent and independent pathways.