Human polyomavirus BKV transcriptionally activates DNA methyltransferase 1 through the pRb/E2F pathway

Abstract

Many DNA tumor virus oncogenes are capable of activating and highjacking the host cell's DNA replication machinery for its own reproduction purposes through targeting and inactivation of the retinoblastoma pocket protein family. Pocket proteins function to regulate cell cycle progression and DNA synthesis through inhibitory interactions with the E2F transcription factors. The interaction of viral oncogenes with the pocket proteins is crucial for their transforming activity. We recently demonstrated that the DNA methyltransferase 1 (DNMT1) gene is an E2F target gene that is transcriptionally activated in cells lacking the retinoblastoma gene (Rb À/À ). Overexpression of DNMT1 is implicated in tumor suppressor gene hypermethylation which is associated with tumorigenesis. Given that viral oncogenes potently stimulate E2F activity, we hypothesized that viral infection might activate DNMT1 and thereby promote transformation. Herein, we demonstrate that DNMT1 is strongly activated by the human polyomavirus BKV large T antigen (TAg) and adenovirus E1a. Viral oncogene mutants incapable of binding the pocket proteins are ineffective at activating DNMT1 compared to their wildtype counterparts. Additionally, mutation of the E2F sites within the DNMT1 promoters dramatically abrogates transcriptional activation. These data suggest that viral induction of DNMT1 through modulation of the pRB/ E2F pathway may be involved in viral transformation.

Histone deacetylase inhibitor apicidin downregulates DNA methyltransferase 1 expression and induces repressive histone modifications via recruitment of corepressor complex to promoter region in human cervix cancer cells

“…Most cervical carcinoma cell lines, including HeLa cells are infected with human papilloma virus and express the E6 and E7 oncoproteins, which bind to and inhibit the p53 and pRB, respectively (Goodwin and DiMaio, 2000). Recently, DNMT1 has been demonstrated to be transcriptionally activated by the human polyomavirus Bradykinin B large T antigen and adenovirus E1a through pRb/E2F pathway (McCabe et al, 2006b). Thus, the apicidin effect could be related to interfering with the function of viral oncoproteins.…”

Viral epigenomes in human tumorigenesis

“…However, a wide range of reports have indicated the presence of viral genomic sequences in multiple human cancers such as osteosarcomas, mesotheliomas, brain tumors, gliomas, medulloblastomas, colorectal carcinomas and skin cancers (Table 1) (Goel et al, 2006;McCabe et al, 2006;Feng et al, 2008;Jiang et al, 2009).…”

“…T antigens are largely responsible for these alterations, and may interact with HATs (p300 and CBP) to enhance or repress gene expression (DeCaprio, 2009), or may induce aberrant methylation, possibly mediated by DNMTs (McCabe et al, 2006), in host gene promoters in several tumor types (Li et al, 2005;Goel et al, 2006).…”

Polyoma virus infection and urothelial carcinoma of the bladder following renal transplantation

“…PV expresses a viral oncogene, the large T-antigen (T-Ag) that inactivates the pocket protein family, including pRb. It has recently been demonstrated that the BKV T-Ag activates the DNA methyltransferase 1 gene -DNMT1 (McCabe et al, 2006). DNMT1 is associated with tumorigenesis through tumour suppressor gene hypermethylation.…”