Adenovirus oncoproteins inactivate the Mre11–Rad50–NBS1 DNA repair complex

Abstract

In mammalian cells, a conserved multiprotein complex of Mre11, Rad50 and NBS1 (also known as nibrin and p95) is important for double-strand break repair, meiotic recombination and telomere maintenance. This complex forms nuclear foci and may be a sensor of double-strand breaks. In the absence of the early region E4, the double-stranded DNA genome of adenovirus is joined into concatemers too large to be packaged. We have investigated the cellular proteins involved in this concatemer formation and how they are inactivated by E4 products during a wild-type infection. Here we show that concatemerization requires functional Mre11 and NBS1, and that these proteins are found at foci adjacent to viral replication centres. Infection with wild-type virus results in both reorganization and degradation of members of the Mre11-Rad50-NBS1 complex. These activities are mediated by three viral oncoproteins that prevent concatemerization. This targeting of cellular proteins involved in genomic stability suggests a mechanism for 'hit-and-run' transformation observed for these viral oncoproteins.

SUMO modification of E1B-55K oncoprotein regulates isoform-specific binding to the tumour suppressor protein PML

“…This possibility is nevertheless fascinating as it would offer a possible explanation for the different transformation capabilities of the large adenovirus E1Bs and earlier suggestions linking nuclear localization of HAdV5 E1B-55K (Endter et al, 2005) and presumably of subgroup HAdV12 E1B-54K (Kra¨tzer et al, 2000) to their oncogenic potential. However, it remains subject for further studies to evaluate how and whether E1B-55K facilitates PML and/or associated proteins to mediate its multiple functions during productive infection involving transcriptional repression of p53 (Yew et al, 1994;Berk, 1998, 1999), selective protein degradation and viral mRNA transport in combination with E4orf6 Querido et al, 2001;Stracker et al, 2002;Baker et al, 2007;Dallaire et al, 2009).…”

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors

“…During retroviral integration, the initial event is detected as DNA damage by the host cell and completion of the integration process requires the DNA protein kinasemediated pathway (Daniel et al, 1999). In another model, adenovirus oncoproteins were found to target cellular proteins involved in the DNA repair process that prevent normal cells from malignancy and regulate genome stability (Stracker et al, 2002). These data, associated with the fact that integration of HPV DNA occurs at a single site in most cases of invasive cervical cancer, indicate that integration is not an incidental event but rather corresponds to an active process.…”

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

“…By studying the ATM signaling pathway after infection with adenovirus, Weitzman and co-workers found that the MRN complex functions upstream of ATM in mammalian cells (Stracker et al, 2002). They showed that the cellular DNA damage response through ATM and ATR is blocked by wildtype adenovirus, which relocalizes and degrades the MRN complex through the action of the viral proteins E1b55K/E4orf6 and E4orf3.…”