Genomic and functional integrity of the hematopoietic system requires tolerance of oxidative DNA lesions

Martín-Pardillos, Ana; Tsaalbi-Shtylik, Anastasia; Chen, Si; Lazare, Seka; Os, Ronald P. van; Dethmers-Ausema, Albertina; Fakouri, Nima Borhan; Bosshard, Matthias; Aprigliano, Rossana; Loon, Barbara van; Salvatori, Daniela; Hashimoto, Keiji; Spek, Celia Dingemanse-van der; Moriya, Masaaki; Rasmussen, Lene Juel; Haan, Gerald de; Raaijmakers, Marc H.G.P.; Wind, Niels de

doi:10.1182/blood-2017-01-764274

Cited by 31 publications

(26 citation statements)

References 60 publications

(70 reference statements)

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“…While most DNA damages are detected and result in cell cycle arrest or apoptosis, some lesions are bypassed via DNA translesion synthesis that appoints specialized DNA polymerases, wherein Rev1 acts as a core factor. Deletion of Rev1 in hematopoietic system led to loss of engraftment potential of HSCs with functional loss starting as early as in the E14 fetal liver . These results clearly emphasize the importance of DDR pathways and predict the effects of DNA damage accumulations.…”

Section: Balance Between Oxidative and Non‐oxidative Pathways Is The Keymentioning

confidence: 64%

Energy Producing Metabolic Pathways in Functional Regulation of the Hematopoietic Stem Cells

et al. 2018

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The hematopoietic system has a very well-studied hierarchy with the long-term (LT) hematopoietic stem cells (HSCs) taking the top position. The pool of quiescent adult LT-HSCs generated during the fetal and early postnatal life acts as a reservoir to supply all the blood cells. Therefore, the maintenance of this stem cell pool is pivotal to maintaining homeostasis in hematopoietic system. It has long been known that external cues, along with the internal genetic factors influence the status of HSCs in the bone marrow (BM). Hypoxia is one such factor that regulates the vascular as well as hematopoietic ontogeny from a very early time point in development. The metabolic outcomes of a hypoxic microenvironment play important roles in functional regulation of HSCs, especially in case of adult BM HSCs. Anaerobic metabolic pathways therefore perform prominent role in meeting energy demands. Increased oxidative pathways on the other hand result in loss of stemness. Recent studies have attributed the functional differences in HSCs across different life stages to their metabolic phenotypes regulated by respective niches. Indicating thus, that various energy production pathways could play distinct role in regulating HSC function at different developmental/physiological states. Here, we review the current status of our understanding over the role that energy production pathways play in regulating HSC stemness. © 2018 IUBMB Life, 70(7):612-624, 2018.

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Section: Balance Between Oxidative and Non‐oxidative Pathways Is The Keymentioning

confidence: 64%

Energy Producing Metabolic Pathways in Functional Regulation of the Hematopoietic Stem Cells

et al. 2018

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“…It has been reported that the expression of Rev1 is upregulated under replication stress (40). In mammalian cells, deletion of REV1 leads to exacerbation of oxidative stress, cell senescence, and apoptosis (41). Furthermore, elevated expression of Rev1 confers enhanced UV damage tolerance (42).…”

Section: Discussionmentioning

confidence: 99%

Sml1 Inhibits the DNA Repair Activity of Rev1 in Saccharomyces cerevisiae during Oxidative Stress

Yao

Zhou

et al. 2020

Appl Environ Microbiol

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In Saccharomyces cerevisiae, Y family DNA polymerase Rev1 is involved in the repair of DNA damage by translesion DNA synthesis (TLS). In the current study, to elucidate the role of Rev1 in oxidative stress-induced DNA damage in S. cerevisiae, REV1 was deleted and overexpressed; transcriptome analysis of these mutants along with the wild-type strain was performed to screen potential genes that could be associated with REV1 during response to DNA damage. When the yeast cells were treated with 2 mM H2O2, the deletion of REV1 resulted in a 1.5- and 2.8-fold decrease in the survival rate and mutation frequency, respectively, whereas overexpression of REV1 increased the survival rate and mutation frequency by 1.1- and 2.9-fold, respectively, compared to the survival rate and mutation frequency of the wild-type strain. Transcriptome and phenotypic analyses identified that Sml1 aggravated oxidative stress in the yeast cells by inhibiting the activity of Rev1. This inhibition was due to the physical interaction between the BRCA1 C terminus (BRCT) domain of Rev1 and amino acid residues 36 to 70 of Sml1; the cell survival rate and mutation frequency increased by 1.8- and 3.1-fold, respectively, when this interaction was blocked. We also found that Sml1 inhibited Rev1 phosphorylation under oxidative stress and that deletion of SML1 increased the phosphorylation of Rev1 by 46%, whereas overexpression of SML1 reduced phosphorylation of Rev1. Overall, these findings demonstrate that Sml1 could be a novel regulator that mediates Rev1 dephosphorylation to inhibit its activity during oxidative stress. IMPORTANCE Rev1 was critical for cell growth in S. cerevisiae, and the deletion of REV1 caused a severe growth defect in cells exposed to oxidative stress (2 mM H2O2). Furthermore, we found that Sml1 physically interacted with Rev1 and inhibited Rev1 phosphorylation, thereby inhibiting Rev1 DNA antioxidant activity. These findings indicate that Sml1 could be a novel regulator for Rev1 in response to DNA damage by oxidative stress.

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“…However, the action of a translesion synthesis DNA polymerase such as REV1, a deoxycytidyl transferase, inserts a cytosine opposite to a uracil, resulting in a C>G transversion 43,44 . Because folate deficiency increases the level of uracil in DNA 45,46 , we propose that it is through the repair of the misincorporated uracil by REV1, present in bone marrow stem cells 47 , that leads to C>G transversions in bone marrow.…”

Section: Discussionmentioning

confidence: 99%

Mutagenicity of folic acid deficiency and supplementation is tissue-specific and results in distinct mutation profiles

Diaz

LeBlanc

Gagné

et al. 2020

Preprint

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Cancer incidence varies by tissue due to differences in environmental risk factor exposure, gene variant inheritance, and lifetime number of stem cell divisions in a tissue. Folate deficiency is associated with increased risk for colorectal cancer (CRC) and acute lymphocytic leukemia. Conversely, high folic acid (FA) intake has been associated with higher CRC risk. However, the mutagenic potential of FA intake in different tissues has not been characterized. Here we quantified mutations in folate-susceptible somatic tissues, namely bone marrow and colon, from the same MutaMouse mice and determined the FA-induced mutation profiles of both tissues using next generation sequencing. FA-induced mutagenesis was tissue- and dose-specific: FA deficiency increased mutant frequency (MF) in bone marrow while FA supplementation increased MF in colon. Analyses of mutation profiles suggested that FA interacted with mutagenic mechanisms that are unique to each tissue. These data illuminate potential mechanisms underpinning differences in susceptibility to FA-related cancers.

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Genomic and functional integrity of the hematopoietic system requires tolerance of oxidative DNA lesions

Abstract: Key Points Tolerance of oxidative DNA lesions ensures the genomic and functional integrity of hematopoietic stem and precursor cells. Endogenous DNA damage–induced replication stress is associated with mitochondrial dysfunction.

Cited by 31 publications

References 60 publications

Energy Producing Metabolic Pathways in Functional Regulation of the Hematopoietic Stem Cells

Energy Producing Metabolic Pathways in Functional Regulation of the Hematopoietic Stem Cells

Sml1 Inhibits the DNA Repair Activity of Rev1 in Saccharomyces cerevisiae during Oxidative Stress

Mutagenicity of folic acid deficiency and supplementation is tissue-specific and results in distinct mutation profiles

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