Stop pulling my strings — what telomeres taught us about the DNA damage response

Denchi, Eros Lazzerini; Sfeir, Agnel

doi:10.1038/nrm.2016.43

Cited by 156 publications

(169 citation statements)

References 202 publications

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“…Instead, at low dose aphidicolin treatment, which mimics replication stress [65], a greater frequency of chromosome segregation defects were found to occur in Tet -TKO ESCs [64]. Tet -TKO mESCs have also been reported to exhibit increased telomere–sister chromatid exchange [43], a mechanism of homologous recombination (HR) and telomere elongation independent of telomerase [66]. A failure to adequately repair DNA damage sustained during S phase can lead to under-replicated regions that interfere with the separation of chromosomes in mitosis [67].…”

Section: Dna Repair and Damage Sensing By Oxi-mcsmentioning

confidence: 99%

Alternative roles for oxidized mCs and TETs

Cimmino

Aifantis

2017

Current Opinion in Genetics & Development

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Ten-eleven-translocation (TET) proteins oxidize 5-methylcytosine (5mC) to form stable or transient modifications (oxi-mCs) in the mammalian genome. Genome-wide mapping and protein interaction studies have shown that 5mC and oxi-mCs have unique distribution patterns and alternative roles in gene expression. In addition, oxi-mCs may interact with specific chromatin regulators, transcription factors and DNA repair proteins to maintain genomic integrity or alter DNA replication and transcriptional elongation rates. In this review we will discuss recent advances in our understanding of how TETs and 5hmC exert their epigenetic function as tumor suppressors by playing alternative roles in transcriptional regulation and genomic stability.

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Section: Dna Repair and Damage Sensing By Oxi-mcsmentioning

confidence: 99%

Alternative roles for oxidized mCs and TETs

Cimmino

Aifantis

2017

Current Opinion in Genetics & Development

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“…Nutrient uptake and utilization are altered in cancer cells in response to oncogenic signaling to promote macromolecular biosynthesis, survival, growth, and proliferation (DeBerardinis and Chandel, 2016; Pavlova and Thompson, 2016). DNA damage also stimulates extensive signaling responses, which direct repair of lesions or, if damage is too extensive, induce cell death (Ciccia and Elledge, 2010; Jackson and Bartek, 2009; Lazzerini-Denchi and Sfeir, 2016). Although the impact of DNA damage signaling on cell metabolism has been less extensively studied than that of growth factor- or oncogene-induced signaling, it is nevertheless clear that metabolism plays key roles in facilitating DNA repair.…”

Section: Introductionmentioning

confidence: 99%

Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination

et al. 2017

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SUMMARY While maintaining the integrity of the genome and sustaining bioenergetics are both fundamental functions of the cell, potential crosstalk between metabolic and DNA repair pathways is poorly understood. Since histone acetylation plays important roles in DNA repair and is sensitive to the availability of acetyl-CoA, we investigated a role for metabolic regulation of histone acetylation during the DNA damage response. In this study, we report that nuclear ATP-citrate lyase (ACLY) is phosphorylated at S455 downstream of ATM and AKT following DNA damage. ACLY facilitates histone acetylation at double strand break (DSB) sites, impairing 53BP1 localization and enabling BRCA1 recruitment and DNA repair by homologous recombination. ACLY phosphorylation and nuclear localization are necessary for its role in promoting BRCA1 recruitment. Upon PARP inhibition, ACLY silencing promotes genomic instability and cell death. Thus, the spatial and temporal control of acetyl-CoA production by ACLY participates in the mechanism of DNA repair pathway choice.

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“…Maintaining proper telomere length is required for cell proliferation. Critically short telomeres trigger a powerful DNA damage response (DDR) that leads to end-to-end chromosome fusion, senescence or cell death (Sandell and Zakian 1993; Longhese 2008 Lazzerini-Denchi and Sfeir 2016). Likewise, ultra-long telomeres limit cell growth and promote tumorigenesis (McEachern and Blackburn 1995; Fairlie and Harrington 2015).…”

Section: Introductionmentioning

confidence: 99%

DDM1 guards against telomere truncation in Arabidopsis

Xie

Shippen

2018

Plant Cell Rep

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Epigenetic pathways, including DNA methylation, are crucial for telomere maintenance. Deficient in DNA Methylation 1 (DDM1) encodes a nucleosome remodeling protein, required to maintain DNA methylation in Arabidopsis thaliana. Plants lacking DDM1 can be self-propagated, but in the sixth generation (G6) hypomethylation leads to rampant transposon activation and infertility. Here we examine the role of DDM1 in telomere length homeostasis through a longitudinal study of successive generations of ddm1-2 mutants. We report that bulk telomere length remains within the wild-type range for the first five generations (G1–G5), and then precipitously drops in G6. While telomerase activity becomes more variable in later generation ddm1-2 mutants, there is no correlation between enzyme activity and telomere length. Plants lacking DDM1 also exhibit no dysregulation of several known telomere-associated transcripts, including TERRA. Instead, telomere shortening coincides with increased G-overhangs and extra-chromosomal circles, consistent with deletional recombination. Telomere shortening also correlates with transcriptional activation of retrotransposons, and a hypersensitive DNA damage response in root apical meristems. Since abiotic stresses, including DNA damage, stimulate homologous recombination, we hypothesize that telomere deletion in G6 ddm1-2 mutants is a by-product of elevated genome-wide recombination in response to trans-poson mobilization. Further, we speculate that telomere truncation may be beneficial in adverse environmental conditions by accelerating the elimination of stem cells with aberrant genomes.

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Stop pulling my strings — what telomeres taught us about the DNA damage response

Cited by 156 publications

References 202 publications

Alternative roles for oxidized mCs and TETs

Alternative roles for oxidized mCs and TETs

Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination

DDM1 guards against telomere truncation in Arabidopsis

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