Genomic instability of the host cell induced by the human papillomavirus replication machinery

Kadaja, Meelis; Sumerina, Alina; Verst, Tatjana; Ojarand, Mari; Ustav, Ene; Ustav, Mart

doi:10.1038/sj.emboj.7601665

Cited by 97 publications

(109 citation statements)

References 60 publications

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“…Consistent with this model, WT T antigen expression can initiate viral DNA replication from integrated viral DNA within an MCC cell, which is expected to lead to replication fork collisions and DNA damage. Similarly, when the papillomavirus E1 helicase protein gene, which is usually lost after integration, is expressed in cervical cancer cells, these cells undergo a DNA damage response (33). Loss of replication capacity thus may be a generalized phenomenon among integrated DNA tumor viruses.…”

Section: Discussionmentioning

confidence: 99%

T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus

Shuda

Feng

Kwun

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

639

908

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Merkel cell polyomavirus (MCV) is a virus discovered in our laboMerkel cell carcinoma ͉ pRB interaction ͉ viral integration ͉ virus replication ͉ helicase M erkel cell carcinoma (MCC) is an aggressive skin cancer associated with sun exposure and immunosuppression (1, 2). Using digital transcriptome subtraction, we recently identified Merkel cell polyomavirus (MCV) as a novel polyomavirus integrated into the genome of MCC tumors (3, 4). The close association between MCV and MCC has been confirmed by others (5). Polyomaviruses are small circular DNA viruses encoding a T antigen oncoprotein locus. T antigens are expressed from variably spliced viral transcripts that target tumor suppressor and cell cycle regulatory proteins, including retinoblastoma tumor suppressor protein (Rb) (6), p53 (7, 8), protein phosphatase 2A (9), and Bub1 (10). Murine polyomavirus (MuPyV) middle T (MT) antigen, a membrane-bound protein, is particularly potent in initiating cell transformation through interactions with phosphatidylinositol 3-kinase, protein phosphatase 2A, Src, and Shc proteins (11,12). MCV large T (LT) antigen retains conserved domains, such as pocket Rb binding LXCXE and DnaJ motifs, present across virus species (13). LT not only encodes tumor suppressor targeting domains but also origin binding and helicase/ATPase functions required for viral genome replication. MCV integration in MCC tumors is incompatible with transmissible virus and likely represents a rare biological accident in which the tumor cell is a dead-end host. The monoclonal pattern of MCV integration into MCC tumors suggests that virus integration occurs before tumor cell expansion and that MCV is a contributing factor in a portion of MCC (3).We have isolated MCV T antigen sequences from both tumor cases and nontumor cases to characterize their abilities to act as a viral DNA replicase. Sequence analysis demonstrates that LT protein is prematurely truncated in all MCC cases, whereas the Rb-interacting domain is preserved. Viruses from nontumor sources do not possess these mutations. We also describe here an MCC cell line stably harboring MCV and an origin replication assay to assess MCV replication. We show that wild type (WT) LT from nontumorous sources activates MCV replication of integrated tumor virus, suggesting that MCV-associated MCC arises from a two-step process in which viral genome integrates into the host genome and develops T antigen mutations to prevent autonomous viral genome replication. Failure to truncate the viral T antigen may lead to DNA damage responses or immune recognition that hinders nascent tumor cell survival.

show abstract

Section: Discussionmentioning

confidence: 99%

T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus

Shuda

Feng

Kwun

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

639

908

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“…The replication forks initiated at the integrated HPV origins extend into the flanking regions of cellular DNA, and these amplified genomic sequences could be targets for the recombination and repair system. This suggests that replication induced from the papillomavirus integrated origin may induce genomic changes of the host cell (Kadaja et al, 2009;Kadaja et al, 2007). Fig.…”

Section: Origin Of Replicationmentioning

confidence: 99%

“…The overall structure of BPV1 and HPV origins is conserved and various combinations of E1 and E2 proteins from different papillomaviruses can initiate DNA replication from several papillomavirus origins (Chiang et al, 1992;Del Vecchio et al, 1992;Kadaja et al, 2007). A relationship appears to exist between the affinity of the E2BS and the ability to function at a distance from the binding site for the E1 protein.…”

Section: Origin Of Replicationmentioning

confidence: 99%

The Role of E2 Proteins in Papillomavirus DNA Replication

Kurg¹

2011

DNA Replication-Current Advances

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“…This may result in doublestranded HPV DNA fragments breaking off of the circular genome and being integrated into the host genome via the endogenous DNA double-strand break (DSB) repair machinery. If the upstream regulatory region is integrated into the host DNA, it may be the site of continued "onion skin" replication as long as the viral E1 and E2 replication proteins are expressed (Kadaja et al, 2007).…”

Section: The Role Of the E7 Proteinmentioning

confidence: 99%