Crosstalk between the mTOR and DNA Damage Response Pathways in Fission Yeast

Cells have developed response systems to constantly monitor environmental changes and accordingly adjust growth, differentiation, and cellular stress programs. The evolutionarily conserved, nutrient-responsive, mechanistic target of rapamycin signaling (mTOR) pathway coordinates basic anabolic and catabolic cellular processes such as gene transcription, protein translation, autophagy, and metabolism, and is directly implicated in cellular and organismal aging as well as age-related diseases. mTOR mediates these processes in response to a broad range of inputs such as oxygen, amino acids, hormones, and energy levels, as well as stresses, including DNA damage. Here, we briefly summarize data relating to the interplays of the mTOR pathway with DNA damage response pathways in fission yeast, a favorite model in cell biology, and how these interactions shape cell decisions, growth, and cell-cycle progression. We, especially, comment on the roles of caffeine-mediated DNA-damage override. Understanding the biology of nutrient response, DNA damage and related pharmacological treatments can lead to the design of interventions towards improved cellular and organismal fitness, health, and survival.

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Viral regulation of host cell biology by hijacking of the nucleolar DNA-damage response

Nature Communications ◽

10.1038/s41467-018-05354-7 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 10

Author(s):

Stephen M. Rawlinson ◽

Tianyue Zhao ◽

Ashley M. Rozario ◽

Christina L. Rootes ◽

Paul J. McMillan ◽

...

Keyword(s):

Dna Damage ◽

Host Cell ◽

Dna Damage Response ◽

Cell Biology ◽

Damage Response

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Guanine Quadruplex DNA Regulates Gamma Radiation Response of Genome Functions in the Radioresistant Bacterium Deinococcus radiodurans

Journal of Bacteriology ◽

10.1128/jb.00154-19 ◽

2019 ◽

Vol 201 (17) ◽

Cited By ~ 2

Author(s):

Shruti Mishra ◽

Reema Chaudhary ◽

Sudhir Singh ◽

Swathi Kota ◽

Hari S. Misra

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Deinococcus Radiodurans ◽

Dna Structure ◽

Protein Translation ◽

Content Type ◽

Cellular Processes ◽

G4 Dna ◽

Guanine Quadruplex ◽

Damage Response

ABSTRACT Guanine quadruplex (G4) DNA/RNA are secondary structures that regulate the various cellular processes in both eukaryotes and bacteria. Deinococcus radiodurans, a Gram-positive bacterium known for its extraordinary radioresistance, shows a genomewide occurrence of putative G4 DNA-forming motifs in its GC-rich genome. N-Methyl mesoporphyrin (NMM), a G4 DNA structure-stabilizing drug, did not affect bacterial growth under normal conditions but inhibited the postirradiation recovery of gamma-irradiated cells. Transcriptome sequencing analysis of cells treated with both radiation and NMM showed repression of gamma radiation-responsive gene expression, which was observed in the absence of NMM. Notably, this effect of NMM on the expression of housekeeping genes involved in other cellular processes was not observed. Stabilization of G4 DNA structures mapped at the upstream of recA and in the encoding region of DR_2199 had negatively affected promoter activity in vivo, DNA synthesis in vitro and protein translation in Escherichia coli host. These results suggested that G4 DNA plays an important role in DNA damage response and in the regulation of expression of the DNA repair proteins required for radioresistance in D. radiodurans. IMPORTANCE Deinococcus radiodurans can recover from extensive DNA damage caused by many genotoxic agents. It lacks LexA/RecA-mediated canonical SOS response. Therefore, the molecular mechanisms underlying the regulation of DNA damage response would be worth investigating in this bacterium. D. radiodurans genome is GC-rich and contains numerous islands of putative guanine quadruplex (G4) DNA structure-forming motifs. Here, we showed that in vivo stabilization of G4 DNA structures can impair DNA damage response processes in D. radiodurans. Essential cellular processes such as transcription, DNA synthesis, and protein translation, which are also an integral part of the double-strand DNA break repair pathway, are affected by the arrest of G4 DNA structure dynamics. Thus, the role of DNA secondary structures in DNA damage response and radioresistance is demonstrated.

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Transcriptional profiling of the age-related response to genotoxic stress points to differential DNA damage response with age

Mechanisms of Ageing and Development ◽

10.1016/j.mad.2009.07.007 ◽

2009 ◽

Vol 130 (9) ◽

pp. 637-647 ◽

Cited By ~ 7

Author(s):

Kirk Simon ◽

Anju Mukundan ◽

Samantha Dewundara ◽

Holly Van Remmen ◽

Alan A. Dombkowski ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Transcriptional Profiling ◽

Genotoxic Stress ◽

Age Related ◽

Damage Response ◽

Related Response

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Identification of S-phase DNA damage-response targets in fission yeast reveals conservation of damage-response networks

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1525620113 ◽

2016 ◽

Vol 113 (26) ◽

pp. E3676-E3685 ◽

Cited By ~ 8

Author(s):

Nicholas A. Willis ◽

Chunshui Zhou ◽

Andrew E. H. Elia ◽

Johanne M. Murray ◽

Antony M. Carr ◽

...

Keyword(s):

Gene Expression ◽

Dna Damage ◽

Dna Replication ◽

Fission Yeast ◽

Dna Damage Response ◽

Cellular Response ◽

Genome Stability ◽

Biological Significance ◽

S Phase ◽

Damage Response

The cellular response to DNA damage during S-phase regulates a complicated network of processes, including cell-cycle progression, gene expression, DNA replication kinetics, and DNA repair. In fission yeast, this S-phase DNA damage response (DDR) is coordinated by two protein kinases: Rad3, the ortholog of mammalian ATR, and Cds1, the ortholog of mammalian Chk2. Although several critical downstream targets of Rad3 and Cds1 have been identified, most of their presumed targets are unknown, including the targets responsible for regulating replication kinetics and coordinating replication and repair. To characterize targets of the S-phase DDR, we identified proteins phosphorylated in response to methyl methanesulfonate (MMS)-induced S-phase DNA damage in wild-type, rad3∆, and cds1∆ cells by proteome-wide mass spectrometry. We found a broad range of S-phase–specific DDR targets involved in gene expression, stress response, regulation of mitosis and cytokinesis, and DNA replication and repair. These targets are highly enriched for proteins required for viability in response to MMS, indicating their biological significance. Furthermore, the regulation of these proteins is similar in fission and budding yeast, across 300 My of evolution, demonstrating a deep conservation of S-phase DDR targets and suggesting that these targets may be critical for maintaining genome stability in response to S-phase DNA damage across eukaryotes.

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G Protein-Coupled Receptor Systems as Crucial Regulators of DNA Damage Response Processes

International Journal of Molecular Sciences ◽

10.3390/ijms19102919 ◽

2018 ◽

Vol 19 (10) ◽

pp. 2919 ◽

Cited By ~ 11

Author(s):

Hanne Leysen ◽

Jaana van Gastel ◽

Jhana Hendrickx ◽

Paula Santos-Otte ◽

Bronwen Martin ◽

...

Keyword(s):

Dna Damage ◽

G Protein ◽

Dna Damage Response ◽

Dna Damage And Repair ◽

Signaling Systems ◽

Age Related ◽

Complex Biological Process ◽

Damage Response ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) and their associated proteins represent one of the most diverse cellular signaling systems involved in both physiological and pathophysiological processes. Aging represents perhaps the most complex biological process in humans and involves a progressive degradation of systemic integrity and physiological resilience. This is in part mediated by age-related aberrations in energy metabolism, mitochondrial function, protein folding and sorting, inflammatory activity and genomic stability. Indeed, an increased rate of unrepaired DNA damage is considered to be one of the ‘hallmarks’ of aging. Over the last two decades our appreciation of the complexity of GPCR signaling systems has expanded their functional signaling repertoire. One such example of this is the incipient role of GPCRs and GPCR-interacting proteins in DNA damage and repair mechanisms. Emerging data now suggest that GPCRs could function as stress sensors for intracellular damage, e.g., oxidative stress. Given this role of GPCRs in the DNA damage response process, coupled to the effective history of drug targeting of these receptors, this suggests that one important future activity of GPCR therapeutics is the rational control of DNA damage repair systems.

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Age-related dysfunction of the DNA damage response in intestinal stem cells

Inflammation and Regeneration ◽

10.1186/s41232-019-0096-y ◽

2019 ◽

Vol 39 (1) ◽

Cited By ~ 4

Author(s):

Koichiro Watanabe ◽

Yasuaki Ikuno ◽

Yumi Kakeya ◽

Shinsuke Ikeno ◽

Hitomi Taniura ◽

...

Keyword(s):

Stem Cells ◽

Dna Damage ◽

Dna Damage Response ◽

Intestinal Stem Cells ◽

Age Related ◽

Damage Response

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Suppression of Akt-mTOR Pathway-A Novel Component of Oncogene Induced DNA Damage Response Barrier in Breast Tumorigenesis

PLoS ONE ◽

10.1371/journal.pone.0097076 ◽

2014 ◽

Vol 9 (5) ◽

pp. e97076 ◽

Cited By ~ 7

Author(s):

Anjana Bhardwaj ◽

Daniel Rosen ◽

Mei Liu ◽

Yan Liu ◽

Qiang Hao ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Mtor Pathway ◽

Breast Tumorigenesis ◽

Damage Response

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Cellular Senescence in Age-Related Macular Degeneration: Can Autophagy and DNA Damage Response Play a Role?

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/5293258 ◽

2017 ◽

Vol 2017 ◽

pp. 1-15 ◽

Cited By ~ 34

Author(s):

Janusz Blasiak ◽

Malgorzata Piechota ◽

Elzbieta Pawlowska ◽

Magdalena Szatkowska ◽

Ewa Sikora ◽

...

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Macular Degeneration ◽

Dna Damage Response ◽

Cellular Senescence ◽

Cell Senescence ◽

Age Related Macular Degeneration ◽

Rpe Cells ◽

Age Related ◽

Damage Response

Age-related macular degeneration (AMD) is the main reason of blindness in developed countries. Aging is the main AMD risk factor. Oxidative stress, inflammation and some genetic factors play a role in AMD pathogenesis. AMD is associated with the degradation of retinal pigment epithelium (RPE) cells, photoreceptors, and choriocapillaris. Lost RPE cells in the central retina can be replaced by their peripheral counterparts. However, if they are senescent, degenerated regions in the macula cannot be regenerated. Oxidative stress, a main factor of AMD pathogenesis, can induce DNA damage response (DDR), autophagy, and cell senescence. Moreover, cell senescence is involved in the pathogenesis of many age-related diseases. Cell senescence is the state of permanent cellular division arrest and concerns only mitotic cells. RPE cells, although quiescent in the retina, can proliferate in vitro. They can also undergo oxidative stress-induced senescence. Therefore, cellular senescence can be considered as an important molecular pathway of AMD pathology, resulting in an inability of the macula to regenerate after degeneration of RPE cells caused by a factor inducing DDR and autophagy. It is too early to speculate about the role of the mutual interplay between cell senescence, autophagy, and DDR, but this subject is worth further studies.

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