Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway

Hoskins, Elizabeth E.; Gunawardena, Ranjaka W.; Habash, Kristen B.; Wise‐Draper, Trisha M.; Jansen, Michael; Knudsen, Erik S.; Wells, Susanne I.

doi:10.1038/onc.2008.121

Cited by 62 publications

(68 citation statements)

References 60 publications

(67 reference statements)

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“…Strikingly, Western blotting shows that both BJ/tert LT and dl89-97 induce the monoubiquitinated FancD2 species in the chromatin fraction (P3), whereas an empty vector does not. A perceptible increase in FancD2 levels is also observed when LT or dl89-97 is expressed; this might result from E2F-mediated transcriptional upregulation by LT (25). Similarly, both BRCA1 and Rad51 are increased (total level) and present in the chromatin fractions for LT and dl89-97, not in the vector control (Fig.…”

Section: Comet Assays Demonstrate That Lt Induces Dna Damagementioning

confidence: 72%

Multiple DNA Damage Signaling and Repair Pathways Deregulated by Simian Virus 40 Large T Antigen

Boichuk

Hein

et al. 2010

J Virol

112

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We demonstrated previously that expression of simian virus 40 (SV40) large T antigen (LT), without a viral origin, is sufficient to induce the hallmarks of a cellular DNA damage response (DDR), such as focal accumulation of ␥-H2AX and 53BP1, via Bub1 binding. Here we expand our characterization of LT effects on the DDR. Using comet assays, we demonstrate that LT induces overt DNA damage. The Fanconi anemia pathway, associated with replication stress, becomes activated, since FancD2 accumulates in foci, and monoubiquitinated FancD2 is detected on chromatin. LT also induces a distinct set of foci of the homologous recombination repair protein Rad51 that are colocalized with Nbs1 and PML. The FancD2 and Rad51 foci require neither Bub1 nor retinoblastoma protein binding. Strikingly, wild-type LT is localized on chromatin at, or near, the Rad51/PML foci, but the LT mutant in Bub1 binding is not localized there. SV40 infection was previously shown to trigger ATM activation, which facilitates viral replication. We demonstrate that productive infection also triggers ATR-dependent Chk1 activation and that Rad51 and FancD2 colocalize with LT in viral replication centers. Using small interfering RNA (siRNA)-mediated knockdown, we demonstrate that Rad51 and, to a lesser extent, FancD2 are required for efficient viral replication in vivo, suggesting that homologous recombination is important for high-level extrachromosomal replication. Taken together, the interplay of LT with the DDR is more complex than anticipated, with individual domains of LT being connected to different subcomponents of the DDR and repair machinery.Simian virus 40 (SV40) carries genes encoding three early proteins: large T antigen (LT), small t antigen, and 17k. LT has served as a powerful model system for understanding cellular processes, such as DNA replication and malignant transformation (1, 16). An in vitro SV40 replication system based on purified cellular factors was established long ago, which in many ways recapitulates in vivo replication (33, 71). However, although very insightful, certain aspects of DNA replication cannot be reconstructed in a test tube and remain incompletely understood. Since SV40 relies extensively on cellular replication factors, it must reprogram the cellular environment to support viral DNA replication. A key component is cell cycle reprogramming, perhaps most importantly the potent induction of S phase in quiescent cells (19).The ability of LT to induce aberrant cellular proliferation depends on binding to and inactivating key tumor suppressors like p53 and the retinoblastoma protein (pRB) family (reviewed in references 1 and 16). These interactions are also critical for oncogenic transformation and induction of tumors in a wide variety of cell types and tissues. Additional functions contribute to transformation. A functional DnaJ domain resides within the first 70 amino acids, which directs binding of the Hsc70 molecular chaperone and contributes to both oncogenic transformation and viral replication proficiency (10, ...

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Section: Comet Assays Demonstrate That Lt Induces Dna Damagementioning

confidence: 72%

Multiple DNA Damage Signaling and Repair Pathways Deregulated by Simian Virus 40 Large T Antigen

Boichuk

Hein

et al. 2010

J Virol

112

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“…2) and, intriguingly, recent work has shown a direct interaction between ATM and FOXO3A at DNA damage foci and invoked a role for FOXO3A in promoting autophosphorylation and activation of ATM in response to damage58. Defects in sensing DNA damage or in homologous recombination involved in repair of double-strand breaks have been previously shown to contribute to diseases in the haematopoietic system59,60 and RB and E2f have been implicated in the transcriptional regulation of several key DNA repair proteins, including FANCD2, MSH2 and RAD51 (REFS 61–63). Furthermore, deficiency for the protein FANCD2 or ataxia telangiectasia and Rad3-related (ATR), both of which are required for cell cycle arrest and repair in response to DNA crosslinking agents, is associated with anaemia and bone marrow failure64,65.…”

Section: Dna Damage and Oxidative Stressmentioning

confidence: 99%

The role of the RB tumour suppressor pathway in oxidative stress responses in the haematopoietic system

Macleod

2008

Nat Rev Cancer

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Exposure to pro-oxidants and defects in the repair of oxidative base damage are associated with disease and ageing and also contribute to the development of anaemia, bone marrow failure and haematopoietic malignancies. This Review assesses emerging data indicative of a specific role for the RB tumour suppressor pathway in the response of the haematopoietic system to oxidative stress. This is mediated through signalling pathways that involve DNA damage sensors, forkhead box O (Foxo) transcription factors and p38 mitogen-activated protein kinases and has downstream consequences for cell cycle progression, antioxidant capacity, mitochondrial mass and cellular metabolism.Mammalian cell cycle checkpoints are activated in response to intracellular and extracellular stresses, such as growth factor deprivation, nucleotide depletion and DNA damage, and the retinoblastoma (RB) tumour suppressor is central in enforcing these checkpoints [1][2][3] . This stress response function of RB is the key to understanding the importance of the BMI1-INK4A-cyclin D-RB-E2f axis in preventing aberrant proliferation and tumour growth [4][5][6] (FIG. 1). The signalling pathways that regulate the dephosphorylation and activation of RB in response to serum deprivation and DNA damage and result in cell cycle arrest are well-described [6][7][8] (BOX 1). In particular, growth factor stimulation of Ras activity promotes activator protein 1-dependent transcriptional induction of cyclin D1, whereas serum-dependent induction of MYC has a similar role for transactivation of cyclin D2 (REF. 9). D-type cyclin expression promotes the activity of cyclin dependent kinase 4 (CDK4) and CDK6 in phosphorylating RB, leading to its inactivation and de-repression of E2f transcription factors 6,10 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript damage shuts down E2f target gene expression by promoting RB dephosphorylation, mediated in part through induction of p53-dependent expression of p21, which binds to and represses CDK2 activity11, and also through the activation of protein phosphatase 2A (PP2A)12 , 13. Recent reports have suggested a link between the accumulation of reactive oxygen species (ROS) and cell cycle progression14, but a mechanistic link between increased levels of ROS and cell cycle control has not been established. New data links increased ROS to activation of the RB pathway in the haematopoietic system and this Review focuses on our current understanding of the role of the BMI1-INK4A-cyclin D-RB-E2f axis in responding to oxidative stress through crosstalk with other regulatory pathways to determine rates of cellular proliferation, stem cell self-renewal and terminal differentiation in the blood system. ROS and the cell cycleROS are highly reactive molecules produced by the one-electron reduction of oxygen. They include oxygen anions, such as superoxide and the hydroxyl radical, as well as hydrogen peroxide and peroxynitrite, which arises from the reaction of superoxide with nitric oxide15 , 16. They are prim...

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“…Previous molecular studies have demonstrated that the HPV E7 oncogene upregulates the transcription and function of these FA proteins (13,27,28). Furthermore, FANCA loss in human keratinocytes caused increased cellular proliferation and hyperplasia in high-risk HPV-positive organotypic epithelial rafts (14).…”

mentioning

confidence: 99%

The Fanconi Anemia Pathway Limits Human Papillomavirus Replication

Hoskins

Morreale

Werner

et al. 2012

J Virol

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k High-risk human papillomaviruses (HPVs) deregulate epidermal differentiation and cause anogenital and head and neck squamous cell carcinomas (SCCs). The E7 gene is considered the predominant viral oncogene and drives proliferation and genome instability. While the implementation of routine screens has greatly reduced the incidence of cervical cancers which are almost exclusively HPV positive, the proportion of HPV-positive head and neck SCCs is on the rise. High levels of HPV oncogene expression and genome load are linked to disease progression, but genetic risk factors that regulate oncogene abundance and/or genome amplification remain poorly understood. Fanconi anemia (FA) is a genome instability syndrome characterized at least in part by extreme susceptibility to SCCs. FA results from mutations in one of 15 genes in the FA pathway, whose protein products assemble in the nucleus and play important roles in DNA damage repair. We report here that loss of FA pathway components FANCA and FANCD2 stimulates E7 protein accumulation in human keratinocytes and causes increased epithelial proliferation and basal cell layer expansion in the HPV-positive epidermis. Additionally, FANCD2 loss stimulates HPV genome amplification in differentiating cells, demonstrating that the intact FA pathway functions to restrict the HPV life cycle. These findings raise the possibility that FA genes suppress HPV infection and disease and suggest possible mechanism(s) for reported associations of HPV with an FA cohort in Brazil and for allelic variation of FA genes with HPV persistence in the general population.H uman papillomaviruses (HPVs) are double-stranded DNA viruses comprised of more than 100 subtypes, some of which, designated high risk, cause cervical and approximately one quarter of head and neck squamous cell carcinomas (HNSCCs) (1,20,21). HPV is associated primarily with HNSCCs that occur in the oropharynx, which includes the back of the tongue, walls of the throat, the soft palate, and the tonsils. Approximately 60% of oropharyngeal SCCs are caused by one of the high-risk types of HPV, and the vast majority of those are positive for HPV type 16 (HPV16) (10). Importantly, these HNSCCs are a distinct type distinguishable from HPV-negative tumors which have alcohol and tobacco use as the predominant risk factors (1).HPV is the causative agent of nearly all cervical cancers and is best studied in that disease. Although HPV infections are common, with up to 90% of women estimated to be infected in their lifetime, most infections are cleared by the immune system and do not progress to cancer. A small fraction of HPV infections, however, lead to low-grade and high-grade squamous intraepithelial lesions and cervical cancer. Persistent infection is the most significant risk factor for developing cervical cancer. While the exact progression of events is still not entirely understood, replication, persistence, integration of the viral genome, and increased expression of the viral E6 and E7 oncogenes are important steps in malignant pro...

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Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway

Cited by 62 publications

References 60 publications

Multiple DNA Damage Signaling and Repair Pathways Deregulated by Simian Virus 40 Large T Antigen

Multiple DNA Damage Signaling and Repair Pathways Deregulated by Simian Virus 40 Large T Antigen

The role of the RB tumour suppressor pathway in oxidative stress responses in the haematopoietic system

The Fanconi Anemia Pathway Limits Human Papillomavirus Replication

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