Published Ahead of Print 14 November 2012.
2013, 87(2):1200. DOI: 10.1128/JVI.02038-12.
Xueli Fan, Yingwang Liu, Susan A. Heilman and Jason J.
Rereplication in Response to DNA Damage
Human Papillomavirus E7 Induces
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Human Papillomavirus E7 Induces Rereplication in Response to DNA
Xueli Fan, Yingwang Liu,* Susan A. Heilman, Jason J. Chen
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
have more than two sets of chromosomes, has been implicated as
a causal factor in tumorigenesis (2, 3). Tetraploidy in basal kera-
tinocytes has been found in low-grade squamous intraepithelial
lesions of the cervix infected with high-risk but not low-risk hu-
strated that tetraploidy occurred as an early event during cervical
carcinogenesis and predisposed cells to aneuploidy that is consis-
tently observed in all cancers (5). Polyploidy can be formed via
rereplication, a process in which origins fire more than once
phases occur without an intervening mitosis (6). Endoreduplica-
term rereplication has often been used for both rereplication and
endoreduplication (6). To reduce confusion, we will use the term
rereplication for DNA rereplication that occurs within the same
interphase and endoreduplication for DNA rereplication that oc-
curs after cells enter into mitosis. Rereplication can lead not only
to polyploidy but also to gene amplification (7), DNA fragmenta-
tion (8), DNA breaks (9), and cellular DNA damage response
(reference 10 and references therein).
Papillomaviruses are small DNA viruses that replicate in the
stratified layers of skin and mucosa. Human papillomaviruses
(HPVs) can be classified as either high or low risk depending on
their clinical associations. The high-risk HPV types, such as
HPV-16 and HPV-18, are commonly associated with lesions that
can progress to high-grade cervical intraepithelial neoplasia and
positive cells (reference 12 and references therein). E6 and E7
from high-risk HPV types induce genomic instability that occurs
early in preneoplastic lesions, when the viral genome still persists
in an episomal state (13, 14). The ability of the high-risk HPV E7
protein to bind and promote the degradation of pRb has been
suggested as a mechanism by which HPV oncogenes promote tu-
enomic instability is a hallmark of cancer progression (1).
Genomic instability in the form of polyploidy, wherein cells
mor formation, although E7 also has functions independent of
inactivating pRb (reviewed in reference 13).
defects contribute to genomic instability (15). The checkpoints in
spindle assembly checkpoint, and the postmitotic checkpoint
(16). The cell cycle is driven mainly by cyclins and cyclin-depen-
dent kinases (Cdks) (17) and is partly controlled by p53 and pRb
(17, 18). Although it is well documented that HPV E7 abrogates
the G1checkpoint (13), its effect on the G2checkpoint is not as
clear. In primary human keratinocytes (PHKs) expressing
HPV-16 E7, an intact G2checkpoint was implicated after treat-
ment with doxorubicin (Adriamycin) (19). However, interpreta-
inhibits topoisomerase II that triggers a decatenation checkpoint
NIH 3T3 cells expressing HPV E7 were thought to be unable to
to60Co, the G2checkpoint is maintained in human fibroblasts
expressing HPV-16 E7 (23). On the other hand, following hy-
droxyurea treatment, more HPV-16 E7-expressing PHKs than
control cells were found in mitosis (24).
We have recently demonstrated that in response to microtu-
bule disruption, E6 and E7 induced polyploidy through en-
doreduplication, a process including cell arrest at the spindle
checkpoint, mitotic slippage, and abrogation of the postmitotic
NIH 3T3 cells treated with doxorubicin was proposed by Polager
Received 5 August 2012 Accepted 5 November 2012
Published ahead of print 14 November 2012
Address correspondence to Jason J. Chen, firstname.lastname@example.org.
*Present address: Yingwang Liu, Department of Cardiology, Xiangya Second
Hospital, Central South University, Changsha, Hunan, China.
Copyright © 2013, American Society for Microbiology. All Rights Reserved.
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