Transcriptional activation of short interspersed elements by DNA‐damaging agents

Abstract

Short interspersed elements (SINEs), typified by the human Alu repeat, are RNA polymerase III (pol III)-transcribed sequences that replicate within the genome through an RNA intermediate. Replication of SINEs has been extensive in mammalian evolution: an estimated 5% of the human genome consists of Alu repeats. The mechanisms regulating transcription, reverse transcription, and reinsertion of SINE elements in genomic DNA are poorly understood. Here we report that expression of murine SINE transcripts of both the B1 and B2 classes is strongly upregulated after prolonged exposure to cisplatin, etoposide, or gamma radiation. A similar induction of Alu transcripts in human cells occurs under these conditions. This induction is not due to a general upregulation of pol III activity in either species. Genotoxic treatment of murine cells containing an exogenous human Alu element induced Alu transcription. Concomitant with the increased expression of SINEs, an increase in cellular reverse transcriptase was observed after exposure to these same DNA-damaging agents. These findings suggest that genomic damage may be an important activator of SINEs, and that SINE mobility may contribute to secondary malignancy after exposure to DNA-damaging chemotherapy.

Identification and Characterization ofSurvival-Related Gene, a Novel Cell Survival Gene Controlling Apoptosis and Tumorigenesis

“…Apoptosis is considered to be a key factor for cancer development (34,35). Disruption of several apoptotic genes has been shown in malignant tumor of many model systems (4,36,37).…”

Identification and Characterization ofSurvival-Related Gene, a Novel Cell Survival Gene Controlling Apoptosis and Tumorigenesis

“…Apoptosis is considered to be a key factor for cancer development (34,35). Disruption of several apoptotic genes has been shown in malignant tumor of many model systems (4,36,37).…”

DNA cleavage and Trp53 differentially affect SINE transcription

“…Genotoxic agents that induce either single-strand (topotecan) or double-strand (etoposide) DNA breaks can induce upregulation of SINE transcript levels. These data are in agreement with experiments performed previously in our laboratory using other agents that induce either single-(UV) or doublestrand (γ-radiation) DNA breaks (Rudin and Thompson, 2001). Conversely, when cells are exposed to cytotoxic agents that are not directly genotoxic (vincristine, paclitaxel, growth factor withdrawal) SINE transcription is not increased.…”

Histone tails: Directing the chromatin response to DNA damage

“…DSB specific forms of DNA damage leads to a global derepression of transposable elements and active transposition of long and short interspersed nuclear elements, LINES and SINES [110]. Similar results are seen during other stress responses.…”

Identification and Characterization ofSurvival-Related Gene, a Novel Cell Survival Gene Controlling Apoptosis and Tumorigenesis

“…Apoptosis is considered to be a key factor for cancer development (34,35). Disruption of several apoptotic genes has been shown in malignant tumor of many model systems (4,36,37).…”

DNA cleavage and Trp53 differentially affect SINE transcription

“…Genotoxic agents that induce either single-strand (topotecan) or double-strand (etoposide) DNA breaks can induce upregulation of SINE transcript levels. These data are in agreement with experiments performed previously in our laboratory using other agents that induce either single-(UV) or doublestrand (γ-radiation) DNA breaks (Rudin and Thompson, 2001). Conversely, when cells are exposed to cytotoxic agents that are not directly genotoxic (vincristine, paclitaxel, growth factor withdrawal) SINE transcription is not increased.…”

Histone tails: Directing the chromatin response to DNA damage

“…DSB specific forms of DNA damage leads to a global derepression of transposable elements and active transposition of long and short interspersed nuclear elements, LINES and SINES [110]. Similar results are seen during other stress responses.…”

Identification and Characterization ofSurvival-Related Gene, a Novel Cell Survival Gene Controlling Apoptosis and Tumorigenesis

“…Apoptosis is considered to be a key factor for cancer development (34,35). Disruption of several apoptotic genes has been shown in malignant tumor of many model systems (4,36,37).…”

DNA cleavage and Trp53 differentially affect SINE transcription

“…Genotoxic agents that induce either single-strand (topotecan) or double-strand (etoposide) DNA breaks can induce upregulation of SINE transcript levels. These data are in agreement with experiments performed previously in our laboratory using other agents that induce either single-(UV) or doublestrand (γ-radiation) DNA breaks (Rudin and Thompson, 2001). Conversely, when cells are exposed to cytotoxic agents that are not directly genotoxic (vincristine, paclitaxel, growth factor withdrawal) SINE transcription is not increased.…”

Histone tails: Directing the chromatin response to DNA damage

“…DSB specific forms of DNA damage leads to a global derepression of transposable elements and active transposition of long and short interspersed nuclear elements, LINES and SINES [110]. Similar results are seen during other stress responses.…”