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Mob DNA. 2016 Dec 7;7:25. eCollection 2016.

The intron-enriched HERV-K(HML-10) family suppresses apoptosis, an indicator of malignant transformation.

Author information

1
Max Planck Institute for molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany ; Institute of Medical Microbiology, University of Zurich, Gloriastr. 32, 8006 Zurich, Switzerland ; Current affiliation: Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany.
2
Max Planck Institute for molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany.
3
Institute of Medical Microbiology, University of Zurich, Gloriastr. 32, 8006 Zurich, Switzerland.
4
Max Planck Institute for molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany ; Current affiliation: University of Zurich, Institute of Molecular Life Sciences, Winterthurerstr. 190, 8057 Zurich, Switzerland.
5
Max Planck Institute for molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany ; Current affiliation: Functional Epigenomics, CCG, Cologne University Hospital, University of Cologne, Weyertal 115b, 50931 Cologne, Germany.
6
Max Planck Institute for molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany ; Dahlem Centre for Genome Research and Medical Systems Biology, Fabeckstr. 60-62, 14195 Berlin, Germany.
7
Max Planck Institute for molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany ; Institute of Medical Microbiology, University of Zurich, Gloriastr. 32, 8006 Zurich, Switzerland.

Abstract

BACKGROUND:

Human endogenous retroviruses (HERVs) constitute 8% of the human genome and contribute substantially to the transcriptome. HERVs have been shown to generate RNAs that modulate host gene expression. However, experimental evidence for an impact of these regulatory transcripts on the cellular phenotype has been lacking.

RESULTS:

We characterized the previously little described HERV-K(HML-10) endogenous retrovirus family on a genome-wide scale. HML-10 invaded the ancestral genome of Old World monkeys about 35 Million years ago and is enriched within introns of human genes when compared to other HERV families. We show that long terminal repeats (LTRs) of HML-10 exhibit variable promoter activity in human cancer cell lines. One identified HML-10 LTR-primed RNA was in opposite orientation to the pro-apoptotic Death-associated protein 3 (DAP3). In HeLa cells, experimental inactivation of HML-10 LTR-primed transcripts induced DAP3 expression levels, which led to apoptosis.

CONCLUSIONS:

Its enrichment within introns suggests that HML-10 may have been evolutionary co-opted for gene regulation more than other HERV families. We demonstrated such a regulatory activity for an HML-10 RNA that suppressed DAP3-mediated apoptosis in HeLa cells. Since HML-10 RNA appears to be upregulated in various tumor cell lines and primary tumor samples, it may contribute to evasion of apoptosis in malignant cells. However, the overall weak expression of HML-10 transcripts described here raises the question whether our result described for HeLa represent a rare event in cancer. A possible function in other cells or tissues requires further investigation.

KEYWORDS:

Apoptosis; Cancer; DAP3; Death-associated protein 3; Endogenous retrovirus; Gene regulation; Genome evolution; HERV; HERV-K(HML-10)

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