Human three prime exonuclease TREX1 is induced by genotoxic stress and involved in protection of glioma and melanoma cells to anticancer drugs.

Abstract

To counteract genotoxic stress, DNA repair functions are in effect. Most of them are constitutively expressed while some of them can be up-regulated depending on the level of DNA damage. In human cells, only few DNA repair functions are subject of induction following DNA damage, and thus there is a need to identify and characterize inducible repair functions more thoroughly. Here, we provide evidence that the "three prime exonuclease I" (TREX1) is up-regulated in human fibroblasts and cancer cells on mRNA and protein level. Transcriptional upregulation of TREX1 was observed upon exposure to ultraviolet light and various anticancer drugs in glioma and malignant melanoma cells. Induction of TREX1 was found following treatment with the crosslinking alkylating agents nimustine, carmustine, fotemustine and the topoisomerase I inhibitor topotecan, but not following temozolomide, etoposide and ionizing radiation. Induction of TREX1 following DNA damage requires the AP-1 components c-Jun and c-Fos, as shown by siRNA knockdown, EMSA experiments, ChIP analysis and reporter assays with the TREX1 promoter and constructs harboring mutations in the AP-1 binding site. To analyze whether TREX1 expression impacts the sensitivity of cancer cells to therapeutics, TREX1 expression was down-regulated by siRNA in malignant glioma and melanoma cells. TREX1 knockdown resulted in enhanced cell death following nimustine, fotemustine and topotecan and to a reduced recovery from the anticancer drug induced block to replication. The data revealed that induction of TREX1 is a survival response evoked by various genotoxic anticancer drugs and identified TREX1 as a potential therapeutic target for anticancer therapy.

• Authors: Maja T Tomicic, Dorthe Aasland, Teodora Nikolova, Bernd Kaina, Markus Christmann
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1833 Issue 8 Pg. 1832-43 (Aug 2013) ISSN: 0006-3002 [Print] Netherlands
• PMID: 23578789 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Phosphoproteins
• Proto-Oncogene Proteins c-fos
• RNA, Messenger
• Transcription Factor AP-1
• Exodeoxyribonucleases
• three prime repair exonuclease 1

Topics

• Antineoplastic Agents (pharmacology)
• Binding Sites (drug effects, genetics)
• Cell Death (drug effects, genetics)
• Cell Line
• Cell Line, Tumor
• DNA Damage (drug effects, genetics)
• DNA Repair (drug effects)
• DNA Replication (drug effects, genetics)
• Down-Regulation (drug effects, genetics)
• Drug Resistance, Neoplasm
• Exodeoxyribonucleases (genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, jun (genetics)
• Glioma (drug therapy, genetics, metabolism)
• Humans
• Melanoma (drug therapy, genetics, metabolism)
• Mutation (drug effects)
• Phosphoproteins (genetics, metabolism)
• Promoter Regions, Genetic (drug effects)
• Proto-Oncogene Proteins c-fos (genetics, metabolism)
• RNA, Messenger (genetics)
• Transcription Factor AP-1 (genetics, metabolism)
• Transcriptional Activation (drug effects, genetics)
• Up-Regulation (drug effects)