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

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.

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

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1717 ◽  
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.

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

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.

scholarly journals MORC2 regulates DNA damage response through a PARP1-dependent pathway

2019 ◽  
Vol 47 (16) ◽  
pp. 8502-8520 ◽  
Author(s):  
Lin Zhang ◽  
Da-Qiang Li
Keyword(s):  
Dna Damage ◽  
Zinc Finger ◽  
Chromatin Remodeling ◽  
Dna Damage Response ◽  
Mammalian Cells ◽  
Cellular Response ◽  
Genotoxic Stress ◽  
Underlying Mechanism ◽  
Dna Lesions ◽  
Damage Response

Abstract Microrchidia family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling enzyme with an emerging role in DNA damage response (DDR), but the underlying mechanism remains largely unknown. Here, we show that poly(ADP-ribose) polymerase 1 (PARP1), a key chromatin-associated enzyme responsible for the synthesis of poly(ADP-ribose) (PAR) polymers in mammalian cells, interacts with and PARylates MORC2 at two residues within its conserved CW-type zinc finger domain. Following DNA damage, PARP1 recruits MORC2 to DNA damage sites and catalyzes MORC2 PARylation, which stimulates its ATPase and chromatin remodeling activities. Mutation of PARylation residues in MORC2 results in reduced cell survival after DNA damage. MORC2, in turn, stabilizes PARP1 through enhancing acetyltransferase NAT10-mediated acetylation of PARP1 at lysine 949, which blocks its ubiquitination at the same residue and subsequent degradation by E3 ubiquitin ligase CHFR. Consequently, depletion of MORC2 or expression of an acetylation-defective PARP1 mutant impairs DNA damage-induced PAR production and PAR-dependent recruitment of DNA repair proteins to DNA lesions, leading to enhanced sensitivity to genotoxic stress. Collectively, these findings uncover a previously unrecognized mechanistic link between MORC2 and PARP1 in the regulation of cellular response to DNA damage.

scholarly journals Hof1 plays a checkpoint-related role in MMS-induced DNA damage response in Candida albicans

2020 ◽  
Vol 31 (5) ◽  
pp. 348-359 ◽  
Author(s):  
Jinrong Feng ◽  
Amjad Islam ◽  
Bjorn Bean ◽  
Jia Feng ◽  
Samantha Sparapani ◽  
...  
Keyword(s):  
Dna Damage ◽  
Candida Albicans ◽  
Mutant Strain ◽  
Dna Damage Response ◽  
Genotoxic Stress ◽  
Dependent Manner ◽  
Damage Response

Fifty-six strains from the GRACE collection were found to be sensitive to MMS upon repression. Deletion of the HOF1 gene renders sensitivity to genotoxic stress. Hof1 is genetically linked to the Rad53 pathway and is down-regulated in a Rad53-dependent manner. The importance of Hof1 in MMS response is reduced in a Rad23 or Rad4 mutant strain.

scholarly journals Modified chromosome structure caused by phosphomimetic H2A modulates the DNA damage response by increasing chromatin mobility in yeast

2021 ◽  
Vol 134 (6) ◽  
Author(s):  
Fabiola García Fernández ◽  
Brenda Lemos ◽  
Yasmine Khalil ◽  
Renaud Batrin ◽  
James E. Haber ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Structural Changes ◽  
Sharp Decrease ◽  
Histone H2a ◽  
End Joining ◽  
Chromatin Dynamics ◽  
Damage Response ◽  
Chromatin Structural ◽  
Non Homologous End Joining

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.

scholarly journals Regulation of DNA Damage Response and Homologous Recombination Repair by microRNA in Human Cells Exposed to Ionizing Radiation

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1838
Author(s):  
Magdalena Szatkowska ◽  
Renata Krupa
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Ionizing Radiation ◽  
Dna Damage Response ◽  
Cell Response ◽  
Dna Lesions ◽  
Homologous Recombination Repair ◽  
Recombination Repair ◽  
Damage Response ◽  
Radiation Induced

Ionizing radiation may be of both artificial and natural origin and causes cellular damage in living organisms. Radioactive isotopes have been used significantly in cancer therapy for many years. The formation of DNA double-strand breaks (DSBs) is the most dangerous effect of ionizing radiation on the cellular level. After irradiation, cells activate a DNA damage response, the molecular path that determines the fate of the cell. As an important element of this, homologous recombination repair is a crucial pathway for the error-free repair of DNA lesions. All components of DNA damage response are regulated by specific microRNAs. MicroRNAs are single-stranded short noncoding RNAs of 20–25 nt in length. They are directly involved in the regulation of gene expression by repressing translation or by cleaving target mRNA. In the present review, we analyze the biological mechanisms by which miRNAs regulate cell response to ionizing radiation-induced double-stranded breaks with an emphasis on DNA repair by homologous recombination, and its main component, the RAD51 recombinase. On the other hand, we discuss the ability of DNA damage response proteins to launch particular miRNA expression and modulate the course of this process. A full understanding of cell response processes to radiation-induced DNA damage will allow us to develop new and more effective methods of ionizing radiation therapy for cancers, and may help to develop methods for preventing the harmful effects of ionizing radiation on healthy organisms.

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

2018 ◽  
Vol 71 (2) ◽  
pp. 332-342.e8 ◽  
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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