Double strand breaks

Pankotai, Tibor; Soutoglou, Evi

doi:10.4161/trns.22879

Cited by 25 publications

(14 citation statements)

References 41 publications

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“…In addition, in response to DNA damage, DNA-PK- (DNA-dependent protein kinase) and ATM-(Ataxia telangiectasia mutated) mediated local inhibition of transcription occurs at the site of the damage, leading to the ubiquitin-mediated degradation of RNAPII7910. In order to demonstrate that, in our experimental setup, the ActD-induced transcription blockage resulted in DNA double-strand breaks (DSBs), we examined the distribution of γH2AX and p53 by immunostaining, 6 and 24 h after ActD treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…If irreversible transcription blockage occurs, the RNAPII is polyubiquitylated and degraded by the 26S proteasome67. The ubiquitin-proteasome system (UPS)-mediated elimination of RNAPII from the site of DNA damage allows the repair of DNA lesions891011. It has been shown that proteins in different DNA damage repair processes, such as CSA (Cockayne syndrome A), BRCA1 (Breast cancer 1), BARD1 complex (BRCA1-associated RING) and NEDD4 (neural precursor cell expressed, developmentally down-regulated 4), are involved in the ubiquitylation of RNAPII121314151617.…”

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confidence: 99%

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Human p53 interacts with the elongating RNAPII complex and is required for the release of actinomycin D induced transcription blockage

Borsos

Huliák

Majoros

et al. 2017

Sci Rep

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The p53 tumour suppressor regulates the transcription initiation of selected genes by binding to specific DNA sequences at their promoters. Here we report a novel role of p53 in transcription elongation in human cells. Our data demonstrate that upon transcription elongation blockage, p53 is associated with genes that have not been reported as its direct targets. p53 could be co-immunoprecipitated with active forms of DNA-directed RNA polymerase II subunit 1 (RPB1), highlighting its association with the elongating RNA polymerase II. During a normal transcription cycle, p53 and RPB1 are localised at distinct regions of selected non-canonical p53 target genes and this pattern of localisation was changed upon blockage of transcription elongation. Additionally, transcription elongation blockage induced the proteasomal degradation of RPB1. Our results reveal a novel role of p53 in human cells during transcription elongation blockage that may facilitate the removal of RNA polymerase II from DNA.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Human p53 interacts with the elongating RNAPII complex and is required for the release of actinomycin D induced transcription blockage

Borsos

Huliák

Majoros

et al. 2017

Sci Rep

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“…We reported previously that transcription arrest in response to DSBs in RNAPII transcribed genes is regulated by DNA-PK activity (Pankotai et al 2012;Pankotai and Soutoglou 2013). Here we demonstrate that DNA-PK activity triggers this process by promoting (1) WWP2-dependent K48-linked ubiquitylation of RPB1, (2) recruitment of the proteasome to broken genes, and (3) proteasomedependent release of RPB1 from broken genes.…”

Section: Cross-talk Of Dna-pk and Wwp2 During Transcription Silencingmentioning

confidence: 99%

WWP2 ubiquitylates RNA polymerase II for DNA-PK-dependent transcription arrest and repair at DNA breaks

et al. 2019

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DNA double-strand breaks (DSBs) at RNA polymerase II (RNAPII) transcribed genes lead to inhibition of transcription. The DNA-dependent protein kinase (DNA-PK) complex plays a pivotal role in transcription inhibition at DSBs by stimulating proteasome-dependent eviction of RNAPII at these lesions. How DNA-PK triggers RNAPII eviction to inhibit transcription at DSBs remains unclear. Here we show that the HECT E3 ubiquitin ligase WWP2 associates with components of the DNA-PK and RNAPII complexes and is recruited to DSBs at RNAPII transcribed genes. In response to DSBs, WWP2 targets the RNAPII subunit RPB1 for K48-linked ubiquitylation, thereby driving DNA-PK- and proteasome-dependent eviction of RNAPII. The lack of WWP2 or expression of nonubiquitylatable RPB1 abrogates the binding of nonhomologous end joining (NHEJ) factors, including DNA-PK and XRCC4/DNA ligase IV, and impairs DSB repair. These findings suggest that WWP2 operates in a DNA-PK-dependent shutoff circuitry for RNAPII clearance that promotes DSB repair by protecting the NHEJ machinery from collision with the transcription machinery.

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“…They may be important for repressing local transcription to prevent passage of RNA Pol II through damaged regions 44; 45; 46; 47 . In addition, repressive structures may temporarily limit the mobility of the damaged chromatin template, reducing nucleosome mobility and forming structures which can keep the DNA ends at the break in close proximity during initial processing of the damage.…”

Section: Nucleosome Dynamics and Dsb Repairmentioning

confidence: 99%

“…This transition from repressive to open chromatin involves several remodeling complexes (discussed in several excellent reviews 3; 5; 45; 56; 57 ). For example, RSC contributes to nucleosome sliding and ejection at DSBs 58; 59 , while FUN30 can regulate resection of the DSB 60; 61 .…”

Section: Transitioning From Repressive To Open Chromatinmentioning

confidence: 99%

Patching Broken DNA: Nucleosome Dynamics and the Repair of DNA Breaks

Gürsoy-Yüzügüllü

House

Price

2016

Journal of Molecular Biology

116

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The ability of cells to detect and repair DNA double-strand breaks (DSBs) is dependent on reorganization of the surrounding chromatin structure by chromatin remodeling complexes. These complexes promote access to the site of DNA damage, facilitate processing of the damaged DNA and, importantly, are essential to repackage the repaired DNA. Here, we will review the chromatin remodeling steps which occur immediately after DSB production and which prepare the damaged chromatin template for processing by the DSB repair machinery. DSBs promote rapid accumulation of repressive complexes, including HP1, the NuRD complex, H2A.Z and histone methyltransferases at the DSB. This shift to a repressive chromatin organization may be important to inhibit local transcription and limit mobility of the break, and to maintain the DNA ends in close contact. Subsequently, the repressive chromatin is rapidly dismantled through a mechanism involving dynamic exchange of the histone variant H2A.Z. H2A.Z removal at DSBs alters the acidic patch on the nucleosome surface, promoting acetylation of the H4 tail (by the NuA4-Tip60 complex) and shifting the chromatin to a more open structure. Further, H2A.Z removal promotes chromatin ubiquitination and recruitment of additional DSB repair proteins to the break. Modulation of the nucleosome surface and nucleosome function during DSB repair therefore plays a vital role in processing of DNA breaks. Further, the nucleosome surface may function as a central hub during DSB repair, directing specific patterns of histone modification, recruiting DNA repair proteins and modulating chromatin packing during processing of the damaged DNA template.

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Double strand breaks

Cited by 25 publications

References 41 publications

Human p53 interacts with the elongating RNAPII complex and is required for the release of actinomycin D induced transcription blockage

Human p53 interacts with the elongating RNAPII complex and is required for the release of actinomycin D induced transcription blockage

WWP2 ubiquitylates RNA polymerase II for DNA-PK-dependent transcription arrest and repair at DNA breaks

Patching Broken DNA: Nucleosome Dynamics and the Repair of DNA Breaks

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