Using or abusing: viruses and the cellular DNA damage response

During infection, viruses attempt to hijack the cell while the host responds with various defense systems. Traditional defenses include the interferon response and apoptosis, but recent work suggests that this antiviral arsenal also includes the cellular DNA damage response machinery. The observation of interactions between viruses and cellular DNA repair proteins has not only uncovered new complexities of the virus-host interaction but is also reinforcing the view that viruses can reveal key regulators of cellular pathways through the proteins they target.     

DNA tumor viruses and human cancer

There is a strong association between viruses and the development of human malignancies. A group of oncogenic DNA viruses exists in the human population today, members of which serve as infectious agents of cancer worldwide. The group includes the Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus, human papillomaviruses and human polyomaviruses. Globally, it is estimated that 20% of all cancers are linked to infectious agents. Studies of DNA viruses have contributed to our current understanding of the key molecular players in the transformation process. Research has also shed light on the molecular mechanisms of tumorigenesis that are employed by these viruses and there are indications that cofactors could be required for viral oncogenicity in some cases.     

At the crossroads of inflammation and cancer

Chronic inflammation and cancer are closely associated in the intestine. Anti-inflammatory medication reduces intestinal neoplasia, while colorectal cancer incidence is increased in ulcerative colitis. Cyclooxygenases are key to both diseases, yet the molecular basis of the association remains incompletely understood. Two recent Cell (Greten et al., 2004; Rakoff-Nahoum et al., 2004) papers illuminate roles of Toll-like receptors and the NF-kappaB pathway in the control of epithelial homeostasis in health and disease.     

Engineering a DNA damage response without DNA damage

Recent work has achieved the feat of activating the DNA damage checkpoint in the absence of DNA damage, revealing the importance of protein-chromatin associations for the activation, amplification and maintenance of the DNA damage response.     

At the crossroads of chemistry and biology

The life sciences are molecular and the harnessing of information gleaned from genomics and proteomics will require interdisciplinary research integrating chemistry and biology. This approach is illustrated by the synthesis and biological evaluation of lipidated peptides and proteins and the delineation of a concept arguing for natural product guided combinatorial chemistry.     

Two sides of the Myc-induced DNA damage response: from tumor suppression to tumor maintenance

ABSTRACT: Activation of oncogenes is generally associated with the induction of DNA damage response (DDR) signaling, which acts as a barrier to tumor progression. In this review we will present an overview of the DDR associated with oncogenic activation of Myc, with special focus on two opposite and paradoxical aspects of this response: (1) the role of the Myc-induced DDR in tumor suppression; (2) its role in dampening Myc-induced replication stress, thereby protecting the viability of prospective cancer cells. These opposing effects on cancer progression are controlled by two different branches of DDR signaling, respectively ATM/CHK2 and ATR/CHK1. Indeed, while ATM activity constitutes a barrier to malignant transformation, full activation of ATR and CHK1 is essential for tumor maintenance, providing important opportunities for therapeutic intervention. Thus, the Myc-induced DDR acts as a double-edged sword in tumor progression.     

Retinoblastoma loss modulates DNA damage response favoring tumor progression

Senescence is one of the main barriers against tumor progression. Oncogenic signals in primary cells result in oncogene-induced senescence (OIS), crucial for protection against cancer development. It has been described in premalignant lesions that OIS requires DNA damage response (DDR) activation, safeguard of the integrity of the genome. Here we demonstrate how the cellular mechanisms involved in oncogenic transformation in a model of glioma uncouple OIS and DDR. We use this tumor type as a paradigm of oncogenic transformation. In human gliomas most of the genetic alterations that have been previously identified result in abnormal activation of cell growth signaling pathways and deregulation of cell cycle, features recapitulated in our model by oncogenic Ras expression and retinoblastoma (Rb) inactivation respectively. In this scenario, the absence of pRb confers a proliferative advantage and activates DDR to a greater extent in a DNA lesion-independent fashion than cells that express only HRas(V12). Moreover, Rb loss inactivates the stress kinase DDR-associated p38MAPK by specific Wip1-dependent dephosphorylation. Thus, Rb loss acts as a switch mediating the transition between premalignant lesions and cancer through DDR modulation. These findings may have important implications for the understanding the biology of gliomas and anticipate a new target, Wip1 phosphatase, for novel therapeutic strategies.     

Cyr61/CCN1 is a tumor suppressor in human hepatocellular carcinoma and involved in DNA damage response

Cyr61/CCN1 is a secreted extracellular matrix associated protein involved in diverse biological functions and plays multiple roles in tumorigenesis. Cyr61 was down-regulated in HCC tumor tissues as observed in our previous cDNA microarray study, but its potential role in hepatocarcinogenesis is still unclear. To explore the biological significance of Cyr61 in HCC development, over-expression of this gene was established in HCC cell lines and its effects on cell proliferation, adhesion, migration and invasion were analyzed in this study. Cyr61 expression was down-regulated in HCC tumors as measured by quantitative real-time PCR and its protein level was decreased in most HCC cell lines as detected by Western blot. Over-expression of Cyr61 in HCC cell lines suppressed cell proliferation in monolayer and anchorage-independent growth in soft agar, whereas down-regulation of Cyr61 by siRNA increased cell proliferation rate. Over-expression of Cyr61 also significantly enhanced adhesion activities of HepG2 cells to various ECM proteins. Moreover, stably transfected HepG2-Cyr61 cells showed inhibited cell mobility (40-45%) and reduced invasiveness (30-40%) compared to HepG2-Neo controls. Furthermore, upon exposure to 5-Fluorouracil and UV irradiation, Cyr61 was rapidly induced in both p53(+/+) HepG2 and p53(-/-) Hep3B cells. However, only HepG2 cells showed increased G2/M phase arrest with concomitant up-regulation in p53 and p21 levels, suggesting that Cyr61 may play an active role in regulating HCC cell growth involving p53 as well as alternative pathways. In conclusion, we demonstrated that Cyr61 is a tumor suppressor in hepatocarcinogenesis and is involved in DNA damage response.     

At the crossroads of ubiquitin signaling and mass spectrometry

Ubiquitin signaling regulates a wide variety of cellular events, although it is mostly known to mediate protein degradation by the proteasome complex. The rapid development in mass spectrometry offers state-of-the-art technologies for addressing biological challenges in ubiquitin signaling. The First Conference on Proteomics of Protein Degradation & Ubiquitin Pathways in Vancouver, Canada, covers the latest progress in key topics of the field and fosters collaborative interactions among researchers.     

Design stars: how small DNA viruses remodel the host nucleus

Numerous host components are encountered by viruses during the infection process. While some of these host structures are left unchanged, others may go through dramatic remodeling processes. In this review, we summarize these host changes that occur during small DNA virus infections, with a focus on host nuclear components and pathways. Although these viruses differ significantly in their genome structures and infectious pathways, there are common nuclear targets that are altered by various viral factors. Accumulating evidence suggests that these nuclear remodeling processes are often essential for productive viral infections and/or viral-induced transformation. Understanding the complex interactions between viruses and these host structures and pathways will help to build a more integrated network of how the virus completes its life cycle and point toward the design of novel therapeutic regimens that either prevent harmful viral infections or employ viruses as nontraditional treatment options or molecular tools.     

Profilin: At the crossroads of signal transduction and the actin cytoskeleton

Despite its small size, profilin is an amazingly diverse and sophisticated protein whose precise role in cells continues to elude the understanding of researchers 15 years after its discovery. Its ubiquity, abundance and necessity for life in more evolved organisms certainly speaks for its exterme importance in cell function. So far, three ligands for profilin have been well-characterized in vitro: actin monomers, membrane polyphosphoinositides and poly-L-proline. In the years following its discovery, profilin's role in vivo progressed from that of a simple actin-binding protein which inhibits actin polymerization, to one which, as an important regulator of the cytoskeleton, can even promote actin polymerization under the appropriate circumstances. In addition, interactions with components of the phosphatidylinositol cycle and the RAS pathway in yeast implicate profilin as an important link through which the actin cytoskeleton is able to communicate with major signaling pathways.     

At the crossroads of ubiquitin signaling and mass spectrometry

Ubiquitin signaling regulates a wide variety of cellular events, although it is mostly known to mediate protein degradation by the proteasome complex. The rapid development in mass spectrometry offers state-of-the-art technologies for addressing biological challenges in ubiquitin signaling. The First Conference on Proteomics of Protein Degradation & Ubiquitin Pathways in Vancouver, Canada, covers the latest progress in key topics of the field and fosters collaborative interactions among researchers.     

Utility of DNA viruses for studying human host history: case study of JC virus

Microbial pathogens, and viruses in particular, can serve as important complements to traditional genetic markers when investigating the population histories of their human host. The range of mutation rates for DNA viruses suggests that DNA viruses can be useful markers of both recent and ancient events in their host histories. Here, we assess the utility of a well known DNA virus, JC virus (JCV), for investigating human history and demography. Using complete coding viral genomes, we confirm the phylogeographic structure of JCV in populations worldwide and provide coalescent estimates of its evolutionary rate under two alternative models of its history. Using these rate estimates, we compare Bayesian skyline plots of population size changes for JCV to those of its human host as estimated with coding mitochondrial genomes of the latter. These comparisons, when combined with other evidence including a log Bayes Factor model test, show that JCV is evolving rapidly and is therefore tracking the recent history of its human host. These results support the hypothesis that post-World War II societal changes are most likely responsible for the recent demographic patterns observed among different regional JCV populations. In sum, fast evolving DNA viruses, such as JCV, can complement RNA viruses to provide novel insights about the recent history and demography of their human host.     

Ubiquitin and the DNA damage response

Comment on: Gatti M, et al. Cell Cycle 2012; 11:2538-44.     

Chromatin and the DNA damage response

The impact of chromatin structure upon the DNA damage response is becoming increasingly apparent. We can reasonably expect many more papers showing how chromatin and chromatin modifications impact upon aspects of the DNA damage response. Here, we present our perspective on some recent developments in this exciting area of cell biology. We aim that this review will be of interest to those who study the DNA damage response, but not usually in the context of chromatin, and equally to those who study chromatin, but not the DNA damage response. It seems likely that these two communities will increasingly share common questions and interests.     

Retroviral DNA integration and the DNA damage response

Retroviral DNA integration creates a discontinuity in the host cell chromatin and repair of this damage is required to complete the integration process. As integration and repair are essential for both viral replication and cell survival, it is possible that specific interactions with the host DNA repair systems might provide new cellular targets for human immunodeficiency virus therapy. Various genetic, pharmacological, and biochemical studies have provided strong evidence that postintegration DNA repair depends on components of the nonhomologous end-joining (NHEJ) pathway (DNA-PK (DNA-dependent protein kinase), Ku, Xrcc4, DNA ligase IV) and DNA damage-sensing pathways (Atr (Atm and Rad related), gamma-H2AX). Furthermore, deficiencies in NHEJ components result in susceptibility to apoptotic cell death following retroviral infection. Here, we review these findings and discuss other ways that retroviral DNA intermediates may interact with the host DNA damage signaling and repair pathways.