Faculty Opinions recommendation of ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks.

ABSTRACT In budding yeast and mammals, double-strand breaks (DSBs) trigger global chromatin mobility together with rapid phosphorylation of histone H2A over an extensive region of the chromatin. To assess the role of H2A phosphorylation in this response to DNA damage, we have constructed strains where H2A has been mutated to the phosphomimetic H2A-S129E. We show that mimicking H2A phosphorylation leads to an increase in global chromatin mobility in the absence of DNA damage. The intrinsic chromatin mobility of H2A-S129E is not due to downstream checkpoint activation, histone degradation or kinetochore anchoring. Rather, the increased intrachromosomal distances observed in the H2A-S129E mutant are consistent with chromatin structural changes. Strikingly, in this context the Rad9-dependent checkpoint becomes dispensable. Moreover, increased chromatin dynamics in the H2A-S129E mutant correlates with improved DSB repair by non-homologous end joining and a sharp decrease in interchromosomal translocation rate. We propose that changes in chromosomal conformation due to H2A phosphorylation are sufficient to modulate the DNA damage response and maintain genome integrity. This article has an associated First Person interview with the first author of the paper.

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MRI Is a DNA Damage Response Adaptor during Classical Non-homologous End Joining

Molecular Cell ◽

10.1016/j.molcel.2018.06.018 ◽

2018 ◽

Vol 71 (2) ◽

pp. 332-342.e8 ◽

Cited By ~ 37

Author(s):

Putzer J. Hung ◽

Britney Johnson ◽

Bo-Ruei Chen ◽

Andrea K. Byrum ◽

Andrea L. Bredemeyer ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

End Joining ◽

Damage Response ◽

Non Homologous End Joining

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The Intermediate Filament Synemin Regulates Non-Homologous End Joining in an ATM-Dependent Manner

Cancers ◽

10.3390/cancers12071717 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1717 ◽

Cited By ~ 3

Author(s):

Sara Sofia Deville ◽

Anne Vehlow ◽

Sarah Förster ◽

Ellen Dickreuter ◽

Kerstin Borgmann ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Dna Damage Response ◽

Intermediate Filament ◽

Intermediate Filament Protein ◽

Dependent Manner ◽

End Joining ◽

Damage Response ◽

Non Homologous End Joining ◽

Filament Protein

The treatment resistance of cancer cells is a multifaceted process in which DNA repair emerged as a potential therapeutic target. DNA repair is predominantly conducted by nuclear events; yet, how extra-nuclear cues impact the DNA damage response is largely unknown. Here, using a high-throughput RNAi-based screen in three-dimensionally-grown cell cultures of head and neck squamous cell carcinoma (HNSCC), we identified novel focal adhesion proteins controlling DNA repair, including the intermediate filament protein, synemin. We demonstrate that synemin critically regulates the DNA damage response by non-homologous end joining repair. Mechanistically, synemin forms a protein complex with DNA-PKcs through its C-terminal tail domain for determining DNA repair processes upstream of this enzyme in an ATM-dependent manner. Our study discovers a critical function of the intermediate filament protein, synemin in the DNA damage response, fundamentally supporting the concept of cytoarchitectural elements as co-regulators of nuclear events.

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Neutrophils Deregulate Tumoral DNA Damage Response and Contribute to Non‐Homologous End‐Joining (NHEJ)‐dependent Survival of Colorectal Cancer

The FASEB Journal ◽

10.1096/fasebj.2020.34.s1.04179 ◽

2020 ◽

Vol 34 (S1) ◽

pp. 1-1

Author(s):

Triet M. Bui

Keyword(s):

Colorectal Cancer ◽

Dna Damage ◽

Dna Damage Response ◽

End Joining ◽

Damage Response ◽

Non Homologous End Joining

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HPF1-dependent histone ADP-ribosylation triggers chromatin relaxation to promote the recruitment of repair factors at sites of DNA damage

10.1101/2021.08.27.457930 ◽

2021 ◽

Author(s):

Rebecca Smith ◽

Siham Zentout ◽

Catherine Chapuis ◽

Gyula Timinszky ◽

Sebastien Huet

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Dna Damage Response ◽

Dna Lesions ◽

End Joining ◽

Adp Ribosylation ◽

Damage Response ◽

Non Homologous End Joining ◽

Chromatin Relaxation ◽

The Impact

PARP1 activity is regulated by its cofactor HPF1. The binding of HPF1 on PARP1 controls the grafting of ADP-ribose moieties on serine residues of proteins nearby the DNA lesions, mainly PARP1 and histones. However, the impact of HPF1 on DNA repair regulated by PARP1 remains unclear. Here, we show that HPF1 controls both the number and the length of the ADP-ribose chains generated by PARP1 at DNA lesions. We demonstrate that HPF1-dependent histone ADP-ribosylation, rather than auto-modification of PARP1, triggers the rapid unfolding of the chromatin structure at the DNA damage sites and promotes the recruitment of the repair factors CHD4 and CHD7. Together with the observation that HPF1 contributes to efficient repair both by homologous recombination and non-homologous end joining, our findings highlight the key roles played by this PARP1 cofactor at early stages of the DNA damage response.

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Functional Roles of Homologous Recombination and Non-Homologous End Joining in DNA Damage Response and Microevolution in Cryptococcus neoformans

Journal of Fungi ◽

10.3390/jof7070566 ◽

2021 ◽

Vol 7 (7) ◽

pp. 566

Author(s):

Kwang-Woo Jung ◽

Jong-Hyun Jung ◽

Ha-Young Park

Keyword(s):

Dna Damage ◽

Homologous Recombination ◽

Cryptococcus Neoformans ◽

Dna Damage Response ◽

Genotoxic Stress ◽

Dna Lesions ◽

Dependent Manner ◽

End Joining ◽

Damage Response ◽

Non Homologous End Joining

DNA double-strand breaks (DSBs) are the most deleterious type of DNA lesions because they cause loss of genetic information if not properly repaired. In eukaryotes, homologous recombination (HR) and non-homologous end joining (NHEJ) are required for DSB repair. However, the relationship of HR and NHEJ in DNA damage stress is unknown in the radiation-resistant fungus Cryptococcus neoformans. In this study, we found that the expression levels of HR- and NHEJ-related genes were highly induced in a Rad53–Bdr1 pathway-dependent manner under genotoxic stress. Deletion of RAD51, which is one of the main components in the HR, resulted in growth under diverse types of DNA damage stress, whereas perturbations of KU70 and KU80, which belong to the NHEJ system, did not affect the genotoxic stresses except when bleomycin was used for treatment. Furthermore, deletion of both RAD51 and KU70/80 renders cells susceptible to oxidative stress. Notably, we found that deletion of RAD51 induced a hypermutator phenotype in the fluctuation assay. In contrast to the fluctuation assay, perturbation of KU70 or KU80 induced rapid microevolution similar to that induced by the deletion of RAD51. Collectively, Rad51-mediated HR and Ku70/Ku80-mediated NHEJ regulate the DNA damage response and maintain genome stability.

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