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TLP-mediated global transcriptional repression after double-strand DNA breaks slows down DNA repair and induces apoptosis
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TLP-mediated global transcriptional repression after double-strand DNA breaks slows down DNA repair and induces apoptosis
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Journal Article
TLP-mediated global transcriptional repression after double-strand DNA breaks slows down DNA repair and induces apoptosis
2019
Overview
Transcription and DNA damage repair act in a coordinated manner. Recent studies have shown that double-strand DNA breaks (DSBs) are repaired in a transcription-coupled manner. Active transcription results in a faster recruitment of DSB repair factors and expedites DNA repair. On the other hand, transcription is repressed by DNA damage through multiple mechanisms. We previously reported that TLP, a TATA box-binding protein (TBP) family member that functions as a transcriptional regulator, is also involved in DNA damage-induced apoptosis. However, the mechanism by which TLP affects DNA damage response was largely unknown. Here we show that TLP-mediated global transcriptional repression after DSBs is crucial for apoptosis induction by DNA-damaging agents such as etoposide and doxorubicin. Compared to control cells, TLP-knockdown cells were resistant to etoposide-induced apoptosis and exhibited an elevated level of global transcription after etoposide exposure. DSBs were efficiently removed in transcriptionally hyperactive TLP-knockdown cells. However, forced transcriptional shutdown using transcriptional inhibitors α-amanitin and 5,6-dichloro-1-ß-D-ribofuranosylbenzimidazole (DRB) slowed down DSB repair and resensitized TLP-knockdown cells to etoposide. Taken together, these results indicate that TLP is a critical determinant as to how cells respond to DSBs and triggers apoptosis to cells that have sustained DNA damage.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 38/89
/ 45/91
/ Alpha-Amanitin - pharmacology
/ Amanitin
/ Autophagy-Related Proteins - antagonists & inhibitors
/ Autophagy-Related Proteins - genetics
/ Dichlororibofuranosylbenzimidazole - pharmacology
/ DNA
/ DNA Breaks, Double-Stranded - drug effects
/ Humanities and Social Sciences
/ Humans
/ Science
/ Tata box
/ Transcription, Genetic - drug effects
/ Transcription, Genetic - genetics
