A DNA-repair pathway can affect transcriptional noise to promote cell fate transitions

Science ◽  
2021 ◽  
pp. eabc6506
Author(s):  
Ravi V. Desai ◽  
Xinyue Chen ◽  
Benjamin Martin ◽  
Sonali Chaturvedi ◽  
Dong Woo Hwang ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cell Fate ◽  
Excision Repair ◽  
Dna Supercoiling ◽  
Cellular Reprogramming ◽  
Transcriptional Noise ◽  
Expression Noise ◽  
Dna Base ◽  
Base Modifications ◽  
Base Excision

Stochastic fluctuations in gene expression (‘noise’) are often considered detrimental, but fluctuations can also be exploited for benefit (e.g., dither). We show here that DNA base-excision repair amplifies transcriptional noise to facilitate cellular reprogramming. Specifically, the DNA-repair protein Apex1, which recognizes both naturally occurring and unnatural base modifications, amplifies expression noise while homeostatically maintaining mean-expression levels. This amplified expression noise originates from shorter duration, higher intensity, transcriptional bursts generated by Apex1-mediated DNA supercoiling. The remodeling of DNA topology first impedes and then accelerates transcription to maintain mean levels. This mechanism, which we term Discordant Transcription through Repair (DiThR; pronounced /’dither’/), potentiates cellular reprogramming and differentiation. Our study reveals a potential functional role for transcriptional fluctuations mediated by DNA base modifications in embryonic development and disease.

scholarly journals Discovery of a Cellular Mechanism Regulating Transcriptional Noise

2020 ◽  
Author(s):  
Ravi V. Desai ◽  
Maike M.K. Hansen ◽  
Benjamin Martin ◽  
Chen Yu ◽  
Sheng Ding ◽  
...  
Keyword(s):  
Single Molecule ◽  
Excision Repair ◽  
Thermal Fluctuations ◽  
Dna Supercoiling ◽  
Cellular Reprogramming ◽  
Transcriptional Noise ◽  
Gene Expression Noise ◽  
Expression Noise ◽  
Base Excision ◽  
Noise Amplification

AbstractStochastic fluctuations in gene expression (‘noise’) are often considered detrimental but, in other fields, fluctuations are harnessed for benefit (e.g., ‘dither’ or amplification of thermal fluctuations to accelerate chemical reactions). Here, we find that DNA base-excision repair amplifies transcriptional noise, generating increased cellular plasticity and facilitating reprogramming. The DNA-repair protein Apex1 recognizes modified nucleoside substrates to amplify expression noise—while homeostatically maintaining mean levels of expression— for virtually all genes across the transcriptome. This noise amplification occurs for both naturally occurring base modifications and unnatural base analogs. Single-molecule imaging shows amplified noise originates from shorter, but more intense, transcriptional bursts that occur via increased DNA supercoiling which first impedes and then accelerates transcription, thereby maintaining mean levels. Strikingly, homeostatic noise amplification potentiates fate-conversion signals during cellular reprogramming. These data suggest a functional role for the observed occurrence of modified bases within DNA in embryonic development and disease.

scholarly journals The Friedreich's ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals

2010 ◽  
Vol 432 (1) ◽  
pp. 165-172 ◽  
Author(s):  
René Thierbach ◽  
Gunnar Drewes ◽  
Markus Fusser ◽  
Anja Voigt ◽  
Doreen Kuhlow ◽  
...  
Keyword(s):  
Dna Repair ◽  
Neurodegenerative Disorder ◽  
Excision Repair ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Liver Tumours ◽  
Dna Repair Mechanisms ◽  
Dna Base ◽  
Repair Mechanisms ◽  
Base Excision

DNA-repair mechanisms enable cells to maintain their genetic information by protecting it from mutations that may cause malignant growth. Recent evidence suggests that specific DNA-repair enzymes contain ISCs (iron–sulfur clusters). The nuclearencoded protein frataxin is essential for the mitochondrial biosynthesis of ISCs. Frataxin deficiency causes a neurodegenerative disorder named Friedreich's ataxia in humans. Various types of cancer occurring at young age are associated with this disease, and hence with frataxin deficiency. Mice carrying a hepatocyte-specific disruption of the frataxin gene develop multiple liver tumours for unresolved reasons. In the present study, we show that frataxin deficiency in murine liver is associated with increased basal levels of oxidative DNA base damage. Accordingly, eukaryotic V79 fibroblasts overexpressing human frataxin show decreased basal levels of these modifications, while prokaryotic Salmonella enterica serotype Typhimurium TA104 strains transformed with human frataxin show decreased mutation rates. The repair rates of oxidative DNA base modifications in V79 cells overexpressing frataxin were significantly higher than in control cells. Lastly, cleavage activity related to the ISC-independent repair enzyme 8-oxoguanine glycosylase was found to be unaltered by frataxin overexpression. These findings indicate that frataxin modulates DNA-repair mechanisms probably due to its impact on ISC-dependent repair proteins, linking mitochondrial dysfunction to DNA repair and tumour initiation.

scholarly journals The Effect of Allopregnanolone on Enzymatic Activity of the DNA Base Excision Repair Pathway in the Sheep Hippocampus and Amygdala under Natural and Stressful Conditions

2020 ◽  
Vol 21 (20) ◽  
pp. 7762
Author(s):  
Tomasz Misztal ◽  
Paweł Kowalczyk ◽  
Patrycja Młotkowska ◽  
Elżbieta Marciniak
Keyword(s):  
Dna Repair ◽  
Enzymatic Activity ◽  
Mrna Expression ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Glycosylase ◽  
Repair Capacity ◽  
Dna Base Excision Repair ◽  
Dna Base ◽  
Base Excision

The neurosteroid allopregnanolone (AL) has many beneficial functions in the brain. This study tested the hypothesis that AL administered for three days into the third brain ventricle would affect the enzymatic activity of the DNA base excision repair (BER) pathway in the hippocampal CA1 and CA3 fields and the central amygdala in luteal-phase sheep under both natural and stressful conditions. Acute stressful stimuli, including isolation and partial movement restriction, were used on the last day of infusion. The results showed that stressful stimuli increased N-methylpurine DNA glycosylase (MPG), thymine DNA glycosylase (TDG), 8-oxoguanine glycosylase (OGG1), and AP-endonuclease 1 (APE1) mRNA expression, as well as repair activities for 1,N6-ethenoadenine (εA), 3,N4-ethenocytosine (εC), and 8-oxoguanine (8-oxoG) compared to controls. The stimulated events were lower in stressed and AL-treated sheep compared to sheep that were only stressed (except MPG mRNA expression in the CA1 and amygdala, as well as TDG mRNA expression in the CA1). AL alone reduced mRNA expression of all DNA repair enzymes (except TDG in the amygdala) relative to controls and other groups. DNA repair activities varied depending on the tissue—AL alone stimulated the excision of εA in the amygdala, εC in the CA3 and amygdala, and 8-oxoG in all tissues studied compared to controls. However, the excision efficiency of lesioned bases in the AL group was lower than in the stressed and stressed and AL-treated groups, with the exception of εA in the amygdala. In conclusion, the presented modulating effect of AL on the synthesis of BER pathway enzymes and their repair capacity, both under natural and stressful conditions, indicates another functional role of this neurosteroid in brain structures.

scholarly journals DNA Base Excision Repair: The Achilles' Heel of Tumour Cells and their Microenvironment?

2017 ◽  
Vol 23 (32) ◽  
pp. 4758-4772 ◽  
Author(s):  
Mattia Poletto ◽  
Arnaud J. Legrand ◽  
Grigory L. Dianov
Keyword(s):  
Dna Repair ◽  
Base Excision Repair ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Treatment Strategies ◽  
Current Status ◽  
Repair System ◽  
Dna Base ◽  
Base Excision ◽  
The Impact

Our current understanding of cancer suggests that every tumour has individual features. Approaches to cancer treatment require thorough comprehension of the mechanisms triggering genomic instability and protecting cancer cells from therapeutic treatments. Base excision repair (BER) is a frontline DNA repair system that is responsible for maintaining genome integrity. The BER pathway prevents the occurrence of disease, including cancer, by constantly repairing DNA base lesions and DNA single strand breaks caused by endogenous and exogenous mutagens. BER is an important DNA repair system for cancer cell survival, as it can affect both chemoand radio-resistance of tumours. Variations in BER capacity are likely responsible for a number of cases of sporadic cancer and may also modulate cancer sensitivity and resistance to therapeutic treatments. For these reasons, it is broadly accepted that targeting BER enzymes might be a promising approach to personalised anti-cancer therapy. However, recent advances in both treatment strategies and the comprehension of cancer development call for a better understanding of the consequences of BER inhibition. Indeed, the impact on both the tumour microenvironment and healthy tissues is still unclear. This review will summarise the current status of the approaches exploiting BER targeting, describing the most promising small molecule inhibitors and synthetic lethality strategies, as well as potential limitations of these approaches.

DNA base excision repair and nucleotide excision repair proteins in malignant salivary gland tumors

2021 ◽  
Vol 121 ◽  
pp. 104987
Author(s):  
Fernanda Aragão Felix ◽  
Leorik Pereira da Silva ◽  
Maria Luiza Diniz de Sousa Lopes ◽  
Ana Paula Veras Sobral ◽  
Roseana de Almeida Freitas ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Nucleotide Excision Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Salivary Gland Tumors ◽  
Dna Base Excision Repair ◽  
Dna Base ◽  
Nucleotide Excision ◽  
Base Excision ◽  
Malignant Salivary Gland Tumors

A Versatile DNA Nanochip for Direct Analysis of DNA Base-Excision Repair

2010 ◽  
Vol 49 (49) ◽  
pp. 9412-9416 ◽  
Author(s):  
Masayuki Endo ◽  
Yousuke Katsuda ◽  
Kumi Hidaka ◽  
Hiroshi Sugiyama
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Direct Analysis ◽  
Dna Base Excision Repair ◽  
Dna Base ◽  
Base Excision

scholarly journals An interaction between the mammalian DNA repair protein XRCC1 and DNA ligase III.

1994 ◽  
Vol 14 (1) ◽  
pp. 68-76 ◽  
Author(s):  
K W Caldecott ◽  
C K McKeown ◽  
J D Tucker ◽  
S Ljungquist ◽  
L H Thompson
Keyword(s):  
Dna Repair ◽  
Affinity Chromatography ◽  
Mammalian Cells ◽  
Excision Repair ◽  
Affinity Purification ◽  
Alkylating Agents ◽  
Chinese Hamster ◽  
Dna Ligase ◽  
Base Excision ◽  
Dna Ligase Iii

XRCC1, the human gene that fully corrects the Chinese hamster ovary DNA repair mutant EM9, encodes a protein involved in the rejoining of DNA single-strand breaks that arise following treatment with alkylating agents or ionizing radiation. In this study, a cDNA minigene encoding oligohistidine-tagged XRCC1 was constructed to facilitate affinity purification of the recombinant protein. This construct, designated pcD2EHX, fully corrected the EM9 phenotype of high sister chromatid exchange, indicating that the histidine tag was not detrimental to XRCC1 activity. Affinity chromatography of extract from EM9 cells transfected with pcD2EHX resulted in the copurification of histidine-tagged XRCC1 and DNA ligase III activity. Neither XRCC1 or DNA ligase III activity was purified during affinity chromatography of extract from EM9 cells transfected with pcD2EX, a cDNA minigene that encodes untagged XRCC1, or extract from wild-type AA8 or untransfected EM9 cells. The copurification of DNA ligase III activity with histidine-tagged XRCC1 suggests that the two proteins are present in the cell as a complex. Furthermore, DNA ligase III activity was present at lower levels in EM9 cells than in AA8 cells and was returned to normal levels in EM9 cells transfected with pcD2EHX or pcD2EX. These findings indicate that XRCC1 is required for normal levels of DNA ligase III activity, and they implicate a major role for this DNA ligase in DNA base excision repair in mammalian cells.

Sign in / Sign up

Export Citation Format

Share Document