DNAPKcs-dependent arrest of RNA polymerase II transcription in the presence of DNA breaks
Open accessAbstract
DNA double-strand break (DSB) repair interferes with ongoing cellular processes, including replication and transcription. Although the process of replication stalling upon collision of replication forks with damaged DNA has been extensively studied, the fate of elongating RNA polymerase II (RNAPII) that encounters a DSB is not well understood. We show that the occurrence of a single DSB at a human RNAPII-transcribed gene leads to inhibition of transcription elongation and reinitiation. Upon inhibition of DNA protein kinase (DNAPK), RNAPII bypasses the break and continues transcription elongation, suggesting that it is not the break per se that inhibits the processivity of RNAPII, but the activity of DNAPK. We also show that the mechanism of DNAPK-mediated transcription inhibition involves the proteasome-dependent pathway. The results point to the pivotal role of DNAPK activity in the eviction of RNAPII from DNA upon encountering a DNA lesion.
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Recent findings demonstrate transcriptional repression in cis to DSBs that depends on DNA damage signaling and ceases after DSB repair is complete.
“Consistent with this, recent findings demonstrate transcriptional repression in cis to DSBs, which depends on DNA damage signaling and ceases after DSB repair is complete (10–13).”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [12]
This prior work on transcriptional repression in cis to DSBs is limited to highly proliferative tumor cell lines, and its implications for animal tissues remain unclear.
“This work is, however, limited to highly proliferative tumor cell lines, and its implications for animal tissues, which often exhibit little or no proliferation, remain unclear.”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [12]
Prior work has shown that DSBs can disrupt expression of genes near breaks in cultured tumor cells.
“DSBs were previously shown to interfere with the expression of break-proximal genes in tumor cell lines (11–13,42).”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [12]
The findings suggest that most tissues can restore DSB-induced gene deregulation, though repair and silencing kinetics may vary with cell type and cell cycle state.
“our findings, thus, suggest that most tissues have the potential to restore DSB-induced gene deregulation, although the kinetics of DSB repair and DNA damage-associated gene silencing may differ depending on cell type and/or cell cycle state.”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [12]
Gene proximity to DSBs did not reliably predict expression changes, except for genes that themselves contained a break.
“the proximity of genes to DSBs did not predictably alter their expression, with the exception of DSB-bearing genes (Figure 3D, E) (12).”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [12]
Several reports link ATM and DNA-PK to repressive chromatin formation and transcriptional silencing near DSBs.
“The latter is in agreement with several reports implicating the DDR mediators ATM and DNA-PK in DSB-proximal repressive chromatin formation as well as transcriptional silencing (9–13,50).”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [12]
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- Authors
- Pankotai, T., Bonhomme, C., Chen, D., & Soutoglou, E.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Soutoglou, Evi
- Venue
- Nature Structural & Molecular Biology
- Published
- 2012-02-12
- Volume
- 19
- Issue
- 3
- Pages
- 276-282
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W2120740595
- Cited by
- 239
- References
- 36
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 21 · 2023: 12 · 2022: 14 · 2021: 24 · 2020: 31 · 2019: 22 · 2018: 10 · 2017: 18 · 2016: 12 · 2015: 18 · 2014: 13 · 2013: 16 · 2012: 5
- FWCI
- 6.67
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- SZTE Publicatio Repozitórium (University of Szeged) (acceptedVersion, other-oa)
- HAL (submittedVersion)
- Funders
- Cancer Research Institute
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale
- Hebrew University of Jerusalem
- Centre National de la Recherche Scientifique
- Institut National Du Cancer
- National Institutes of Health (CA50519)
- National Cancer Institute (CA 50519)
- Institute of Genetics
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- DNA double-strand breaks, RNA polymerase II, transcription elongation, transcription reinitiation, proteasome, transcriptional arrest, DNA damage response, transcription-coupled repair, transcribed genes
- MeSH terms
- Ku Autoantigen, Cell Line, DNA-Binding Proteins, Humans, Nuclear Proteins, RNA Polymerase II, Transcription, Genetic, Antigens, Nuclear, DNA-Activated Protein Kinase, DNA Breaks, Double-Stranded
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