H3K4me2 regulates the recovery of protein biosynthesis and homeostasis following DNA damage

Wang, Siyao; Meyer, David H.; Schumacher, Björn

doi:10.1038/s41594-020-00513-1

Cited by 35 publications

(32 citation statements)

References 70 publications

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“…We started with previously established signatures of adult glioblastomas, composed of key effectors of the cell cycle as well as components of crucial DNA repair factors [ 22 ]. Although our data show that the signatures established in aGBMs can indeed capture features related to cell cycle and DNA repair in pHGG tumors, the observed segregation did not correlate with underlying driver mutations affecting histones, as shown in previous studies [ 18 , 20 , 21 , 31 , 32 , 33 ]. Our efforts to identify a specific DNA repair and cell cycle gene expression signature of pHGGs led to a 28-gene expression signature that was able to cluster the sus-tentorial and thalamic pHGG group effectively.…”

Section: Discussioncontrasting

confidence: 63%

“…In those DIPG, histone H3 demethylase inhibition using GSK-14 enhanced the efficiency of IR by inhibiting DSB repair by HR [ 19 ]. In contrast, H3.3 G34 mutants were found to display increased genomic instability and replicative stress, as well as a defective HR-mediated repair [ 20 , 21 ]. In aGBM, a novel classification was recently achieved using unique DNA repair and cell cycle gene expression signatures exposing vulnerabilities to DNA damaging agents and inhibitors of the DNA damage response [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

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A DNA Repair and Cell Cycle Gene Expression Signature in Pediatric High-Grade Gliomas: Prognostic and Therapeutic Value

Entz‐Werlé¹,

Poidevin

Nazarov

et al. 2021

Cancers

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Background: Pediatric high-grade gliomas (pHGGs) are the leading cause of mortality in pediatric neuro-oncology, displaying frequent resistance to standard therapies. Profiling DNA repair and cell cycle gene expression has recently been proposed as a strategy to classify adult glioblastomas. To improve our understanding of the DNA damage response pathways that operate in pHGGs and the vulnerabilities that these pathways might expose, we sought to identify and characterize a specific DNA repair and cell-cycle gene expression signature of pHGGs. Methods: Transcriptomic analyses were performed to identify a DNA repair and cell-cycle gene expression signature able to discriminate pHGGs (n = 6) from low-grade gliomas (n = 10). This signature was compared to related signatures already established. We used the pHGG signature to explore already transcriptomic datasets of DIPGs and sus-tentorial pHGGs. Finally, we examined the expression of key proteins of the pHGG signature in 21 pHGG diagnostic samples and nine paired relapses. Functional inhibition of one DNA repair factor was carried out in four patients who derived H3.3 K27M mutant cell lines. Results: We identified a 28-gene expression signature of DNA repair and cell cycle that clustered pHGGs cohorts, in particular sus-tentorial locations, in two groups. Differential protein expression levels of PARP1 and XRCC1 were associated to TP53 mutations and TOP2A amplification and linked significantly to the more radioresistant pHGGs displaying the worst outcome. Using patient-derived cell lines, we showed that the PARP-1/XRCC1 expression balance might be correlated with resistance to PARP1 inhibition. Conclusion: We provide evidence that PARP1 overexpression, associated to XRCC1 expression, TP53 mutations, and TOP2A amplification, is a new theranostic and potential therapeutic target.

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Section: Discussioncontrasting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

A DNA Repair and Cell Cycle Gene Expression Signature in Pediatric High-Grade Gliomas: Prognostic and Therapeutic Value

Entz‐Werlé¹,

Poidevin

Nazarov

et al. 2021

Cancers

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“…8 ). Additionally, both H3K79 methylation and H3K4 methylation have been linked to transcription restart after UV in mouse cells 27 , and C. elegans 51 . Whether these histone marks are deposited in a PAF1-dependent manner remains to be addressed.…”

Section: Discussionmentioning

confidence: 99%

A CSB-PAF1C axis restores processive transcription elongation after DNA damage repair

et al. 2021

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Bulky DNA lesions in transcribed strands block RNA polymerase II (RNAPII) elongation and induce a genome-wide transcriptional arrest. The transcription-coupled repair (TCR) pathway efficiently removes transcription-blocking DNA lesions, but how transcription is restored in the genome following DNA repair remains unresolved. Here, we find that the TCR-specific CSB protein loads the PAF1 complex (PAF1C) onto RNAPII in promoter-proximal regions in response to DNA damage. Although dispensable for TCR-mediated repair, PAF1C is essential for transcription recovery after UV irradiation. We find that PAF1C promotes RNAPII pause release in promoter-proximal regions and subsequently acts as a processivity factor that stimulates transcription elongation throughout genes. Our findings expose the molecular basis for a non-canonical PAF1C-dependent pathway that restores transcription throughout the human genome after genotoxic stress.

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“…Björn Schumacher, University of Cologne, Germany, characterized molecular consequences of DNA damage either in germline or somatic cells [34,35] and examined molecular pathways that regulate somatic maintenance using C. elegans as a model organism. His recent discovery of epigenetic modifiers that are required for maintaining lifespan after DNA damage [36] shed light on novel molecular pathways linking DNA damage, epigenetics and longevity. A connection between DNA damage/repair, post-translational modifications and longevity was also presented by Vera Gorbunova, University of Rochester, USA, who applies a comparative biology approach to study short-and long-lived animals.…”

Section: Genome Maintenance In Aging and Longevitymentioning

confidence: 99%

ARDD 2020: from aging mechanisms to interventions

Mkrtchyan

Abdelmohsen

Andreux

et al. 2020

Aging

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H3K4me2 regulates the recovery of protein biosynthesis and homeostasis following DNA damage

Cited by 35 publications

References 70 publications

A DNA Repair and Cell Cycle Gene Expression Signature in Pediatric High-Grade Gliomas: Prognostic and Therapeutic Value

A DNA Repair and Cell Cycle Gene Expression Signature in Pediatric High-Grade Gliomas: Prognostic and Therapeutic Value

A CSB-PAF1C axis restores processive transcription elongation after DNA damage repair

ARDD 2020: from aging mechanisms to interventions

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