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Tumor Biology |
Department of Pathology and Harvard Center for Cancer Biology, Harvard Medical School, Boston, Massachusetts 02115
The development of genomic instability is a hallmark of high-risk human papillomavirus (HPV) associated cervical carcinogenesis. We have previously shown that the HPV-16 E7 oncoprotein rapidly subverts mitotic fidelity by inducing abnormal centrosome numbers and multipolar mitotic spindles. Here we report that expression of HPV-16 E6 and E7 independently results in various mitotic abnormalities. HPV-16 E6 and E7 were each associated with unaligned or lagging chromosomal material, indicating relaxation of spindle checkpoint control. Moreover, by overwhelming checkpoint control mechanisms that may prevent cells with multiple spindle poles to enter anaphase, expression of HPV-16 E6 and E7 leads to a small but significant number of cells with altered polarity at later stages of the cell division process. In addition to changes that have the potential to give rise to numerical chromosome imbalances, we discovered that expression of HPV-16 E7 could trigger anaphase bridge formation to an extent similar to that of high-risk HPV E6. Anaphase bridges typically develop after chromosomal breaks and alterations of chromosomal structure. Further investigation of mechanisms by which HPV-16 E6 and E7 contribute to the destabilization of the host cell genome revealed that both high-risk HPV oncoproteins induce DNA damage. Moreover, expression of HPV-16 E7 was associated with an increased number of cells exhibiting nuclear foci of phosphorylated histone H2AX as well as activation of cell cycle checkpoints triggered by DNA repair. Our results therefore suggest that HPV oncoproteins are a source for both numerical and structural chromosome instability during HPV-associated carcinogenesis.
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