Insight into the ERVK Integrase – Propensity for DNA Damage

Bray, S. L.; Turnbull, Matthew; Hebert, Sherry; Douville, Renée N.

doi:10.3389/fmicb.2016.01941

Cited by 10 publications

(18 citation statements)

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“…Based on homology modeling, we predict that the ERVK IN enzyme contains all the essential motifs and domain structures for retroviral IN function [ 22 ]. A recombinant ERVK-10 integrase enzyme also confirms that it has the potential for strand-transfer activity [ 23 ]. A remaining question is how ERVK IN interacts with cellular proteins and pathways, as has been shown for many other retroviral integrases [ 19 , 24 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 94%

Predicted Cellular Interactors of the Endogenous Retrovirus-K Integrase Enzyme

2021

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Integrase (IN) enzymes are found in all retroviruses and are crucial in the retroviral integration process. Many studies have revealed how exogenous IN enzymes, such as the human immunodeficiency virus (HIV) IN, contribute to altered cellular function. However, the same consideration has not been given to viral IN originating from symbionts within our own DNA. Endogenous retrovirus-K (ERVK) is pathologically associated with neurological and inflammatory diseases along with several cancers. The ERVK IN interactome is unknown, and the question of how conserved the ERVK IN protein–protein interaction motifs are as compared to other retroviral integrases is addressed in this paper. The ERVK IN protein sequence was analyzed using the Eukaryotic Linear Motif (ELM) database, and the results are compared to ELMs of other betaretroviral INs and similar eukaryotic INs. A list of putative ERVK IN cellular protein interactors was curated from the ELM list and submitted for STRING analysis to generate an ERVK IN interactome. KEGG analysis was used to identify key pathways potentially influenced by ERVK IN. It was determined that the ERVK IN potentially interacts with cellular proteins involved in the DNA damage response (DDR), cell cycle, immunity, inflammation, cell signaling, selective autophagy, and intracellular trafficking. The most prominent pathway identified was viral carcinogenesis, in addition to select cancers, neurological diseases, and diabetic complications. This potentiates the role of ERVK IN in these pathologies via protein–protein interactions facilitating alterations in key disease pathways.

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Section: Introductionmentioning

confidence: 94%

Predicted Cellular Interactors of the Endogenous Retrovirus-K Integrase Enzyme

2021

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“…Those HML-2 RT enzymes were strictly dependent on Mg2 +, and did not show polymerase activity with other divalent cations (Berkhout et al 1999). The integrase of HML-2 (HERV-K10) has also been cloned; it showed both terminal cleavage and strand transfer in the presence of Mn2 + of the HML-2 LTR substrate (Kitamura et al 1996; Bray et al 2016). In the human genome (GRCh38) only 8 HML-2 proviruses have intact integrase motifs (Bray et al 2016).…”

Section: Hml-2 Structure: Genes Transcripts and Proteinsmentioning

confidence: 99%

Human endogenous retrovirus-K (HML-2): a comprehensive review

García-Montojo

Doucet-O’Hare

Henderson

et al. 2018

Critical Reviews in Microbiology

161

164

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The human genome contains a large number of retroviral elements acquired over the process of evolution, some of which are specific to primates. However, as many of these are defective or silenced through epigenetic changes, they were historically considered “junk DNA” and their potential role in human physiology or pathological circumstances have been poorly studied. The most recently acquired, human endogenous retrovirus-K (HERV-K), has multiple copies in the human genome and some of them have complete open reading frames that are transcribed and translated, especially in early embryogenesis. Phylogenetically, HERV-K is considered a supergroup of viruses. One of the subtypes, termed HML-2, seems to be the most active and hence, it is the best studied. Aberrant expression of HML-2 in adult tissues has been associated with certain types of cancer and with neurodegenerative diseases. This review discusses the discovery of these viruses, their classification, structure, regulation and potential for replication, physiological roles, and their involvement in disease pathogenesis. Finally, it presents different therapeutic approaches being considered to target these viruses.

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“…Enzymatic activity of retroviral integrase proteins can lead to significant DNA damage accumulation over time (49). Given a loss of DNA repair function in SBMA, this may render cells more vulnerable to DNA damaging insults like ERVK integrase activity (21) (unpublished data). Therefore, our observation of mature ERVK integrase protein expression in PBMC from patients with AR polyQ repeats is potentially pathologically relevant to the underlying multi-system disease processes that occur in SBMA.…”

Section: Discussionmentioning

confidence: 99%

Expression of Human Endogenous Retrovirus-K in Spinal and Bulbar Muscular Atrophy

et al. 2019

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Background: Spinal and Bulbar Muscular Atrophy (SBMA) is caused by the extension of the polyglutamine tract within the androgen receptor (AR) gene, and results in a multisystem presentation, including the degeneration of lower motor neurons. The androgen receptor (AR) is known to modulate the expression of endogenous retrovirus-K (ERVK), a pathogenic viral genomic symbiont. Since ERVK is associated with motor neuron disease, such as Amyotrophic Lateral Sclerosis (ALS), we sought to determine if patients with SBMA exhibit evidence of ERVK reactivation.Results: Data from a pilot study demonstrate that peripheral blood mononuclear cell (PBMC) samples from controls and patients with SBMA were examined ex vivo for the expression of ERVK viral transcripts and proteins. No differences in ERVK RNA expression was observed between the clinical groups. In contrast, enhancement of processed ERVK Gag and integrase proteins were observed in SBMA-derived PBMC as compared to healthy control specimens. Increased ERVK protein maturation co-occurred with elevation in the expression of the pro-inflammatory transcription factor IRF1 in SBMA.Conclusions: Our findings indicate that ERVK viral protein maturation in SBMA is an unrecognized biomarker and facet of the disease. We discuss how our current understanding of ERVK-driven pathology may tie into key aspects of multi-system dysfunction in SBMA, with a focus on inflammation, proteinopathy, as well as DNA damage and repair.

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Insight into the ERVK Integrase – Propensity for DNA Damage

Cited by 10 publications

References 58 publications

Predicted Cellular Interactors of the Endogenous Retrovirus-K Integrase Enzyme

Predicted Cellular Interactors of the Endogenous Retrovirus-K Integrase Enzyme

Human endogenous retrovirus-K (HML-2): a comprehensive review

Expression of Human Endogenous Retrovirus-K in Spinal and Bulbar Muscular Atrophy

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