The tripartite motif (TRIM) family of proteins is an evolutionarily ancient group of proteins with homologues identified in both invertebrate and vertebrate species. Human TRIM22 is one such protein that has a dynamic evolutionary history that includes gene expansion, gene loss, and strong signatures of positive selection. To date, TRIM22 has been shown to restrict the replication of a number of viruses, including encephalomyocarditis virus (EMCV), hepatitis B virus (HBV), and human immunodeficiency virus type 1 (HIV-1). In addition, TRIM22 has also been implicated in cellular differentiation and proliferation and may play a role in certain cancers and autoimmune diseases. This comprehensive paper summarizes our current understanding of TRIM22 structure and function.

Clayton J. Hattlmann

Jenna N. Kelly

Stephen D. Barr

TRIM22: A Diverse and Dynamic Antiviral Protein

The RASSF family of proteins has been extensively studied in terms of their genetics, structure and function. One of the functions that has been increasingly studied is the role of the RASSF proteins in the DNA damage response. Surprisingly, this research, which encompasses both the classical and N-terminal RASSF proteins, has revealed an involvement of the RASSFs in oncogenic pathways as well as the more familiar tumour suppressor pathways usually associated with the RASSF family members. The most studied protein with respect to DNA damage is RASSF1A, which has been shown, not only to be activated by ATM, a major regulator of the DNA damage response, but also to bind to and activate a number of different pathways which all lead to and feedback from the guardian of the genome, p53. In this review we discuss the latest research linking the RASSF proteins to DNA damage signalling and maintenance of genomic integrity and look at how this knowledge is being utilised in the clinic to enhance the effectiveness of traditional cancer therapies such as radiotherapy.

Simon F. Scrace

Eric O'Neill

RASSF Signalling and DNA Damage: Monitoring the Integrity of the Genome?

The RASSF proteins are a family of polypeptides, each containing a conserved Ras association domain, suggesting that these scaffold proteins may be effectors of activated Ras or Ras-related small GTPases. RASSF proteins are characterized by their ability to inhibit cell growth and proliferation while promoting cell death. RASSF1 isoform A is an established tumor suppressor and is frequently silenced in a variety of tumors and human cancer cell lines. However, our understanding of its function in terminally differentiated cell types, such as cardiac myocytes, is relatively nascent. Herein, we review the role of RASSF1A in cardiac physiology and disease and highlight signaling pathways that mediate its function.

Dominic P. Del Re

Junichi Sadoshima

RASSF1A Signaling in the Heart: Novel Functions beyond Tumor Suppression

The Ras association domain family 1A (RASSF1A) tumor suppressor encodes a Sav-RASSF-Hpo domain (SARAH), which is an interaction domain characterized by hWW45 (dSAV) and MST1/2 (dHpo). In our study, the interaction between RASSF1A and RASSF1C with MST1 and MST2 was demonstrated and it was shown that this interaction depends on the SARAH domain. SARAH domain-deleted RASSF1A had a similar growth-reducing effect as full-length RASSF1A and inhibited anchorage independent growth of the lung cancer cell lines A549 significantly. In cancer cells expressing the SARAH deleted form of RASSF1A, reduced mitotic rates (<svg     style="vertical-align:-0.1638pt;width:66.875px;" id="M1" height="11.375" version="1.1" viewBox="0 0 66.875 11.375" width="66.875"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,11.112)"><path id="x1D443" d="M619 482q0 -69 -40.5 -119t-96 -72.5t-118.5 -26.5h-44l-70 20l-31 -151q-14 -67 0.5 -83t89.5 -22l-5 -28h-287l8 28q65 7 81.5 22t29.5 83l79 398q12 56 0.5 70.5t-78.5 20.5l7 28h255q108 0 164 -43t56 -125zM524 478q0 141 -146 141q-25 0 -47 -8q-16 -6 -20.5 -13.5&#xA;t-10.5 -39.5l-43 -241q37 -13 83 -13q67 0 125.5 45t58.5 129z" /></g><g transform="matrix(.017,-0,0,-.017,15.582,11.112)"><path id="x3D" d="M535 323h-483v50h483v-50zM535 138h-483v50h483v-50z" /></g><g transform="matrix(.017,-0,0,-.017,30.286,11.112)"><path id="x30" d="M241 635q53 0 94 -28.5t63.5 -76t33.5 -102.5t11 -116q0 -58 -11 -112.5t-34 -103.5t-63.5 -78.5t-94.5 -29.5t-95 28t-64.5 75t-34.5 102.5t-11 118.5q0 58 11.5 112.5t34.5 103t64.5 78t95.5 29.5zM238 602q-32 0 -55.5 -25t-35.5 -68t-17.5 -91t-5.5 -105&#xA;q0 -76 10 -138.5t37 -107.5t69 -45q32 0 55.5 25t35.5 68.5t17.5 91.5t5.5 105t-5.5 105.5t-18 92t-36 68t-56.5 24.5z" /></g><g transform="matrix(.017,-0,0,-.017,38.446,11.112)"><path id="x2E" d="M113 -12q-24 0 -39.5 16t-15.5 42q0 24 16 40.5t40 16.5t40 -16.5t16 -40.5q0 -26 -16 -42t-41 -16z" /></g><g transform="matrix(.017,-0,0,-.017,42.321,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,50.481,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,58.64,11.112)"><path id="x31" d="M384 0h-275v27q67 5 81.5 18.5t14.5 68.5v385q0 38 -7.5 47.5t-40.5 10.5l-48 2v24q85 15 178 52v-521q0 -55 14.5 -68.5t82.5 -18.5v-27z" /></g>

		
	
</svg>) with abnormal metaphases (<svg     style="vertical-align:-0.1638pt;width:66.875px;" id="M2" height="11.375" version="1.1" viewBox="0 0 66.875 11.375" width="66.875"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,11.112)"><use xlink:href="#x1D443"/></g><g transform="matrix(.017,-0,0,-.017,15.582,11.112)"><path id="x3C" d="M512 -3l-437 233v51l437 233v-58l-378 -200v-2l378 -199v-58z" /></g><g transform="matrix(.017,-0,0,-.017,30.286,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,38.446,11.112)"><use xlink:href="#x2E"/></g><g transform="matrix(.017,-0,0,-.017,42.321,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,50.481,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,58.64,11.112)"><use xlink:href="#x31"/></g>

		
	
</svg>) were observed and a significantly increased rate of apoptosis was found (<svg     style="vertical-align:-0.1638pt;width:66.875px;" id="M3" height="11.375" version="1.1" viewBox="0 0 66.875 11.375" width="66.875"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,11.112)"><use xlink:href="#x1D443"/></g><g transform="matrix(.017,-0,0,-.017,15.582,11.112)"><use xlink:href="#x3D"/></g><g transform="matrix(.017,-0,0,-.017,30.286,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,38.446,11.112)"><use xlink:href="#x2E"/></g><g transform="matrix(.017,-0,0,-.017,42.321,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,50.481,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,58.64,11.112)"><path id="x36" d="M137 343l67 33q37 17 63 17q79 0 129.5 -53t50.5 -131q0 -92 -58 -156.5t-147 -64.5t-147 68t-58 182q0 63 17 119t43 95.5t61.5 72t69 52t67.5 31.5q62 22 128 33l6 -32q-56 -11 -108 -35q-149 -71 -184 -231zM227 337q-47 0 -95 -27q-6 -23 -6 -70q0 -93 36 -155.5&#xA;t96 -62.5q53 0 78 45.5t25 105.5q0 68 -35 116t-99 48z" /></g>

		
	
</svg>) compared to full-length RASSF1A. Although the association with microtubules and their stabilization was unaffected, mitotic spindle formation was altered by deletion of the SARAH domain of RASSF1A. In summary, our results suggest that the SARAH domain plays an important role in regulating the function of RASSF1A.

Claudia Dittfeld

Antje M. Richter

Katrin Steinmann

Antje Klagge-Ulonska

Reinhard H. Dammann

The SARAH Domain of RASSF1A and Its Tumor Suppressor Function

The RASSF1A tumor suppressor gene is frequently inactivated by promoter methylation in human tumors. The RASSF1A protein forms an endogenous complex with tubulin and promotes the stabilization of microtubules. Loss of RASSF1A expression sensitizes cells to microtubule destabilizing stimuli. We have observed a strong correlation between the loss of RASSF1A expression and the development of Taxol resistance in primary ovarian cancer samples. Thus, we sought to determine if RASSF1A levels could dictate the response to Taxol and whether an epigenetic therapy approach might be able to reverse the Taxol resistant phenotype of RASSF1A negative ovarian tumor cells. We found that knocking down RASSF1A expression in an ovarian cancer cell line inhibited Taxol-mediated apoptosis and promoted cell survival during Taxol treatment. Moreover, using a combination of small molecule inhibitors of DNA Methyl Transferase enzymes, we were able restore RASSF1A expression and Taxol sensitivity. This identifies a role for RASSF1A in modulating the tumor response to Taxol and provides proof of principal for the use of epigenetic therapy to overcome Taxol resistance.

Susannah Kassler

Howard Donninger

Michael J. Birrer

Geoffrey J. Clark

RASSF1A and the Taxol Response in Ovarian Cancer

Hepatocellular carcinoma (HCC) is one of the most frequent solid tumors worldwide, with limited treatment options and a dismal prognosis. Thus, there is a strong need to expand the basic and translational research on this deadly disease in order to improve the prognosis of HCC patients. Although the etiologic factors responsible for HCC development have been identified, the molecular pathogenesis of liver cancer remains poorly understood. Recent evidence has shown the frequent downregulation of Ras association domain family (RASSF) proteins both in the early and late stages of hepatocarcinogenesis. Here, we summarize the data available on the pathogenetic role of inactivation of RASSF proteins in liver cancer, the molecular mechanisms responsible for suppression of RASSF proteins in HCC, and the possible clinical implications arising from these discoveries. Altogether, the data indicate that inactivation of the RASSF1A tumor suppressor is ubiquitous in human liver cancer, while downregulation of RASSF2 and RASSF5 proteins is limited to specific HCC subsets. Also, the present findings speak in favour of therapeutic strategies aimed at reexpressing <i>RASSF1A</i>, <i>RASSF2</i>, and <i>RASSF5</i> genes and/or inactivating the RASSF cellular inhibitors for the treatment of human liver cancer.

Diego F. Calvisi

Matthias Evert

Frank Dombrowski

Pathogenetic and Prognostic Significance of Inactivation of RASSF Proteins in Human Hepatocellular Carcinoma

Fr&#xe9;d&#xe9;ric Coin

Bernardo Reina-San-Martin

Giuseppina Giglia-Mari

Mark Berneburg

DNA in 3R: Repair, Replication, and Recombination

Promoter hypermethylation, a widely studied epigenetic event known to influence gene expression levels, has been proposed as a potential biomarker in multiple types of cancer. Clinical diagnostic biomarkers are needed for reliable prediction of bladder cancer recurrence. In this paper, DNA promoter methylation of five C-terminal Ras-association family members (<i>RASSF1A, RASSF2A, RASSF4, RASSF5</i>, and <i>RASSF6</i>) was studied in 64 formalin-fixed paraffin-embedded (FFPE) bladder cancer and normal adjacent tissues using methylation-specific high-resolution melting (MS-HRM) analysis. Results showed that 73% (30/41) of transitional cell carcinoma, 100% (3/3) of squamous cell carcinoma, and 100% (4/4) of small cell carcinoma demonstrated promoter methylation of the <i>RASSF1A</i> or <i>RASSF2A</i> gene, but only 6% (1/16) of normal tissues had promoter methylation of <i>RASSF</i> genes. Testing positive for hypermethylation of <i>RASSF1A</i> or <i>RASSF2A</i> promoter provided 77% sensitivity and 94% specificity for identification of cancer tissues with an area under the curve of 0.854, suggesting that promoter methylation analysis of <i>RASSF1A</i> and <i>RASSF2A</i> genes has potential for use as a recurrence biomarker for bladder cancer patients.

Wei Meng

Alexander Huebner

Ahmad Shabsigh

Arnab Chakravarti

Tim Lautenschlaeger

Combined <i>RASSF1A</i> and <i>RASSF2A</i> Promoter Methylation Analysis as Diagnostic Biomarker for Bladder Cancer

Genotoxicity studies in Ecuador have been carried out during the past two decades. The focuses of the research were mainly the area of environmental issues, where the populations have been accidentally exposed to contaminants and the area of occupational exposure of individuals at the workplace. This paper includes studies carried out in the population of the Amazon region, a zone known for its rich biodiversity as well as for the ecological damage caused by oil spills and chemical sprayings whose consequences continue to be controversial. Additionally, we show the results of studies comprised of individuals occupationally exposed to toxic agents in two very different settings: flower plantation workers exposed to pesticide mixtures and X-ray exposure of hospital workers. The results from these studies confirm that genotoxicity studies can help evaluate current conditions and prevent further damage in the populations exposed to contaminants. As such, they are evidence of the need for biomonitoring employers at risk, stricter law enforcement regarding the use of pesticides, and increasingly conscientious oil extraction activities.

C&#233;sar Paz-y-Mi&#241;o

Nadia Cumbal

Mar&#237;a Eugenia S&#225;nchez

Genotoxicity Studies Performed in the Ecuadorian Population

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