HPV 5 and 8 E6 expression reduces ATM protein levels and attenuates LINE-1 retrotransposition

- HPV 5 and 8 E6 expression results in diminished steady state ATM protein levels.
- This reduction is dependent on the promotion of p300 degradation by HPV 5 and 8 E6.
- HPV 5 and 8 E6 restrict the retrotransposition of LINE-1.
- Efficient LINE-1 retrotransposition requires ATM kinase activity.
- LINE-1 ORF2 retains the ability to induce DSBs in an ATM -/- background.

The expression of the E6 protein from certain members of the HPV genus β (β HPV 5 and 8 E6) can disrupt p53 signaling by diminishing the steady state levels of two p53 modifying enzymes, ATR and p300. Here, we show that β-HPV 5 and 8 E6 are also capable of reducing the steady state levels of another p53 modifying enzyme, ATM, and as a result restrict LINE-1 retrotransposition. Furthermore, we show that the reduction of both ATM and LINE-1 retrotransposition is dependent upon the ability of β-HPV 8 E6 to bind and degrade p300. We use inhibitors and dominant negative mutants to confirm that ATM is needed for efficient LINE-1 retrotransposition. Furthermore, neither sensitivity to LINE-1 expression nor LINE-1 induced DSB formation is altered in an ATM deficient background. Together, these data illustrate the broad impact some β-HPVs have on DNA damage signaling by promoting p300 degradation.