DNA Damage Responses during the Cell Cycle: Insights from Model Organisms and Beyond

Clay, Delisa E; Fox, Donald T.

doi:10.3390/genes12121882

Cited by 32 publications

(13 citation statements)

References 168 publications

(209 reference statements)

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“…Some researchers believe that somatic polyploidy is harmful as it slows down proliferation, inhibits regeneration, reduces cell functionality and promotes genetic instability [ 69 , 83 , 84 , 85 , 86 , 87 , 88 ]. Others think that additional genomes are useful as they enhance cell function due to the acceleration of metabolic processes, protein synthesis, regenerative properties, and protect cells from oncogenic transformation [ 1 , 3 , 89 , 90 ].…”

Section: Somatic Polyploidymentioning

confidence: 99%

“…The analysis of gene expression in the human and mouse hepatocytes, cardiomyocytes, trophoblast cells, neurons, adipose mesenchymal stem cells, interstitial cardiac stem cells, drosophila epithelial cells, and various types of cancer cells indicate that polyploidy can exert both common and specific effects [ 7 , 69 , 73 , 78 , 83 , 84 , 110 , 111 , 112 ]. The common effects are the induction of biological pathways related to stress response (i.e., abiotic, biotic, hypoxic, oxidative, genotoxic, and inflammatory), response to DNA instability, and drug resistance [ 7 , 57 , 69 , 72 , 83 , 87 , 113 , 114 , 115 ]. Polyploidy also activates the signaling cascades involved in embryogenesis (including Notch, TGFb, Hippo, Myc, EGFR, and WNT) and the growth-related gene modules implicated in stemness, DNA synthesis, glycolysis, and ribosome biogenesis [ 1 , 7 , 11 , 72 , 74 , 77 , 78 , 110 , 111 , 112 , 116 ].…”

Section: Ploidy-associated Transcriptome Features Are Related To Stre...mentioning

confidence: 99%

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Polyploidy as a Fundamental Phenomenon in Evolution, Development, Adaptation and Diseases

Anatskaya

Vinogradov

2022

IJMS

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DNA replication during cell proliferation is ‘vertical’ copying, which reproduces an initial amount of genetic information. Polyploidy, which results from whole-genome duplication, is a fundamental complement to vertical copying. Both organismal and cell polyploidy can emerge via premature cell cycle exit or via cell-cell fusion, the latter giving rise to polyploid hybrid organisms and epigenetic hybrids of somatic cells. Polyploidy-related increase in biological plasticity, adaptation, and stress resistance manifests in evolution, development, regeneration, aging, oncogenesis, and cardiovascular diseases. Despite the prevalence in nature and importance for medicine, agri- and aquaculture, biological processes and epigenetic mechanisms underlying these fundamental features largely remain unknown. The evolutionarily conserved features of polyploidy include activation of transcription, response to stress, DNA damage and hypoxia, and induction of programs of morphogenesis, unicellularity, and longevity, suggesting that these common features confer adaptive plasticity, viability, and stress resistance to polyploid cells and organisms. By increasing cell viability, polyploidization can provide survival under stressful conditions where diploid cells cannot survive. However, in somatic cells it occurs at the expense of specific function, thus promoting developmental programming of adult cardiovascular diseases and increasing the risk of cancer. Notably, genes arising via evolutionary polyploidization are heavily involved in cancer and other diseases. Ploidy-related changes of gene expression presumably originate from chromatin modifications and the derepression of bivalent genes. The provided evidence elucidates the role of polyploidy in evolution, development, aging, and carcinogenesis, and may contribute to the development of new strategies for promoting regeneration and preventing cardiovascular diseases and cancer.

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Section: Somatic Polyploidymentioning

confidence: 99%

Section: Ploidy-associated Transcriptome Features Are Related To Stre...mentioning

confidence: 99%

Polyploidy as a Fundamental Phenomenon in Evolution, Development, Adaptation and Diseases

Anatskaya

Vinogradov

2022

IJMS

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“…[ 1,4–6 ] In response, eukaryotic cells have evolved the DNA replication checkpoint pathway to efficiently discover and deal with replication stress events. [ 7–13 ]…”

Section: Introductionmentioning

confidence: 99%

“…[1,[4][5][6] In response, eukaryotic cells have evolved the DNA replication checkpoint pathway to efficiently discover and deal with replication stress events. [7][8][9][10][11][12][13] Abbreviations: AID, auxin-inducible degron; BrdU-IP-ssSeq, 5′-bromo-2′-deoxyuridine immunoprecipitation followed by strand-specific sequencing; ChIP-ssSeq, chromatin immunoprecipitation followed by strand-specific sequencing; eSPAN, enrichment and sequencing of protein-associated nascent DNA; HU, hydroxyurea; ssDNA, single-stranded DNA.…”

Section: Introductionmentioning

confidence: 99%

Rad53 arrests leading and lagging strand DNA synthesis via distinct mechanisms in response to DNA replication stress

Zhang

2022

BioEssays

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DNA replication stress threatens ordinary DNA synthesis. The evolutionarily conserved DNA replication stress response pathway involves sensor kinase Mec1/ATR, adaptor protein Mrc1/Claspin, and effector kinase Rad53/Chk1, which spurs a host of changes to stabilize replication forks and maintain genome integrity. DNA replication forks consist of largely distinct sets of proteins at leading and lagging strands that function autonomously in DNA synthesis in vitro. In this article, we discuss eSPAN and BrdU‐IP‐ssSeq, strand‐specific sequencing technologies that permit analysis of protein localization and DNA synthesis at individual strands in budding yeast. Using these approaches, we show that under replication stress Rad53 stalls DNA synthesis on both leading and lagging strands. On lagging strands, it stimulates PCNA unloading, and on leading strands, it attenuates the replication function of Mrc1‐Tof1. We propose that in doing so, Rad53 couples leading and lagging strand DNA synthesis during replication stress, thereby preventing the emergence of harmful ssDNA.

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“…The conservation of critical FA proteins across various species emphasizes the importance of the pathway in maintaining genomic stability. This conservation necessitates further development of accessible genetic models to shed light on FA pathway mechanisms ( Rodríguez and D’Andrea 2017 ; Niraj et al 2019 ; Clay and Fox 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Conserved function ofDrosophilaFancd2 monoubiquitination in response to double-strand DNA breaks

Clay

Jezuit

Montague

et al. 2022

G3 Genes|Genomes|Genetics

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Fanconi anemia genes play key roles in metazoan DNA damage responses, and human FA mutations cause numerous disease phenotypes. In human cells, activating monoubiquitination of the Fanconi anemia protein Fancd2 occurs following diverse DNA damage stimuli. Monoubiquitinated Fancd2 forms nuclear foci to recruit additional repair factors. Fancd2 animal models to date have focused on molecular nulls or whole gene knockdown, leaving the specific in vivo role of monoubiquitination unclear. Using a point mutant in a conserved residue, we recently linked Drosophila Fancd2 monoubiquitination to a mitosis-specific DNA double-strand break response. In this context, we used CRISPR/Cas9 to generate the first animal model of an endogenous mutation in the conserved monoubiquitination site (fancd2K595R). Here, we expand upon our characterization of fancd2K595R. We also introduce and characterize additional Drosophila tools to study fancd2, including new mutant alleles and GFP-tagged rescue transgenes. Using these new reagents, we show the impact of Drosophila Fancd2 on organismal and cell viability, as well as on repair protein localization, in the presence or absence of double-strand breaks. These findings expand our understanding of Fanconi anemia gene function in vivo and provide useful reagents for DNA repair research.

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DNA Damage Responses during the Cell Cycle: Insights from Model Organisms and Beyond

Cited by 32 publications

References 168 publications

Polyploidy as a Fundamental Phenomenon in Evolution, Development, Adaptation and Diseases

Polyploidy as a Fundamental Phenomenon in Evolution, Development, Adaptation and Diseases

Rad53 arrests leading and lagging strand DNA synthesis via distinct mechanisms in response to DNA replication stress

Conserved function ofDrosophilaFancd2 monoubiquitination in response to double-strand DNA breaks

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