Metabolic modulation of chromatin: implications for DNA repair and genomic integrity

Liu, Jinping; Kim, Jeongkyu; Oberdoerffer, Philipp

doi:10.3389/fgene.2013.00182

Cited by 23 publications

(28 citation statements)

References 110 publications

(165 reference statements)

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“…Alterations in NAD + levels modulate DNA repair and NAD + is elevated under conditions of nutrient deprivation. NAD + -dependent P enzymes [poly(ADP-ribose) polymerase (PARP)1 and PARP2] are immediately activated in response to DNA DSBs and function to regulate both nonhomologous end joining and homologous recombination (30). In our study, PARP1 gene expression was shown to be elevated in fasted etoposide-treated mice compared with their fed counterparts (Dataset S2).…”

Section: Crypt Stem Cells Maintain Integrity Of the Si In Fasted Micementioning

confidence: 68%

“…Many of the chromatin-modifying enzymes involved in DNA repair depend on metabolic intermediates as cofactors for their activity, thereby directly linking changes in cellular metabolism with DNA repair (30). Interestingly, high levels of NAD + (nicotinamide adenine dinucleotide) correlate with radioprotection of human glioma cells (31).…”

Section: Crypt Stem Cells Maintain Integrity Of the Si In Fasted Micementioning

confidence: 99%

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Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival

Tinkum

Stemler

White

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Short-term fasting protects mice from lethal doses of chemotherapy through undetermined mechanisms. Herein, we demonstrate that fasting preserves small intestinal (SI) architecture by maintaining SI stem cell viability and SI barrier function following exposure to highdose etoposide. Nearly all SI stem cells were lost in fed mice, whereas fasting promoted sufficient SI stem cell survival to preserve SI integrity after etoposide treatment. Lineage tracing demonstrated that multiple SI stem cell populations, marked by Lgr5, Bmi1, or HopX expression, contributed to fasting-induced survival. DNA repair and DNA damage response genes were elevated in SI stem/progenitor cells of fasted etoposide-treated mice, which importantly correlated with faster resolution of DNA double-strand breaks and less apoptosis. Thus, fasting preserved SI stem cell viability as well as SI architecture and barrier function suggesting that fasting may reduce host toxicity in patients undergoing dose intensive chemotherapy.stem cells | DNA damage | chemotherapy | fasting C ancer patients undergoing chemotherapy experience high rates of morbidity, despite regimens that attempt to balance timing and dose intensity to mitigate off-target effects and doselimiting toxicities (1-3). Interestingly, fasting has been shown to provide host-protective effects against high-dose chemotherapyinduced toxicity in preclinical and clinical studies. For example, etoposide, which forms a ternary complex with DNA and topoisomerase II causing DNA double-strand breaks (DSBs), is far less toxic if mice are fasted before treatment (4). Fasting has also been shown to protect normal, but not cancer cells, from the toxicity of chemotherapy, thereby extending the lifespan of tumorbearing mice (4-8).Because of the rapid rate of epithelial cell proliferation in the small intestine (SI), gastrointestinal (GI) toxicity is one of the most common complications for a variety of chemotherapeutic treatments (9). Therefore, we investigated if fasting was capable of mitigating the GI toxicity normally associated with high-dose chemotherapy. Herein, we demonstrate that mice allowed to feed ad libitum before receiving high-dose chemotherapy showed marked histological changes to SI epithelium before death. These histological changes reflected loss of regenerative capacity as a result of stem cell depletion as well as structural damage from inflammatory cell infiltrates, similar to the SI response to high-dose ionizing radiation (10). In contrast, SI homeostasis was preserved in fasted mice by protection of stem cell viability and prevention of proinflammatory cell infiltrates. These results indicate that fasting mitigates GI side effects associated with chemotherapy by activating pathways that preserve SI stem cell integrity and by maintaining barrier function.

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Section: Crypt Stem Cells Maintain Integrity Of the Si In Fasted Micementioning

confidence: 68%

Section: Crypt Stem Cells Maintain Integrity Of the Si In Fasted Micementioning

confidence: 99%

Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival

Tinkum

Stemler

White

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The importance of accumulated DNA damage in ageing is illustrated by several progeroid phenotypes, which are induced by mutations in DNA repair enzymes 136 , although it is unclear whether increased DNA repair itself can extend lifespan. Interestingly, metabolites linked to the regulation of longevity, such as NAD or α-ketoglutarate, modulate the activity of proteins involved in both DNA repair and chromatin remodeling 137 . For example, the recruitment of NAD-dependent deacetylases SIRT1 and SIRT6 may directly promote genomic stability 69, 70, 73, 74 .…”

Section: Epigenetics and Genomic Stability In Ageingmentioning

confidence: 99%

Epigenetic regulation of ageing: linking environmental inputs to genomic stability

Benayoun

Pollina

Brunet

2015

Nat Rev Mol Cell Biol

536

430

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Preface Ageing is affected by both genetic and non-genetic factors. Here, we review the chromatin-based epigenetic changes that occur during ageing, the role of chromatin modifiers in modulating lifespan and the importance of epigenetic signatures as biomarkers of ageing. We also discuss how epigenome remodeling by environmental stimuli impacts several aspects of transcription and genomic stability, with important consequences on longevity, and outline epigenetic differences between the ‘mortal soma’ and the ‘immortal germline’. Finally, we discuss the inheritance of ageing characteristics and potential chromatin-based strategies to delay or reverse hallmarks of ageing or age-related diseases.

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“…Epigenetic modifications play a major role in tissue- and cell-type-specific differences in gene expression (100, 138) and many other cellular processes (73, 131, 137). The role of epigenetics in disease is well established in the field of cancer (10, 34) and imprinting disorders (8).…”

Section: Figurementioning

confidence: 99%

Mendelian Disorders of the Epigenetic Machinery: Tipping the Balance of Chromatin States

Fahrner

Björnsson

2014

Annu. Rev. Genom. Hum. Genet.

139

132

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Mendelian disorders of the epigenetic machinery are a newly delineated group of multiple congenital anomaly and intellectual disability syndromes resulting from mutations in genes encoding components of the epigenetic machinery. The gene products affected in these inherited conditions act in trans and are expected to have widespread epigenetic consequences. Many of these syndromes demonstrate phenotypic overlap with classical imprinting disorders and with one another. The various writer and eraser systems involve opposing players, which we propose must maintain a balance between open and closed chromatin states in any given cell. An imbalance might lead to disrupted expression of disease-relevant target genes. We suggest that classifying disorders based on predicted effects on this balance would be informative regarding pathogenesis. Furthermore, strategies targeted at restoring this balance might offer novel therapeutic avenues, taking advantage of available agents such as histone deacetylase inhibitors and histone acetylation antagonists.

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Metabolic modulation of chromatin: implications for DNA repair and genomic integrity

Cited by 23 publications

References 110 publications

Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival

Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival

Epigenetic regulation of ageing: linking environmental inputs to genomic stability

Mendelian Disorders of the Epigenetic Machinery: Tipping the Balance of Chromatin States

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