Epigenetics and DNA Damage

Front Cover
Epigenetics and DNA Damage
Copyright
Contents
Contributors
Preface
Section 1: Understanding the relationship between DNA damage and epigenetic mechanisms
Chapter 1: DNA damage and DNA methylation
Introduction
Base modifications
DNA methylation
Deamination
Alkylation
Oxidation
Cross-links
DNA methylation and DNA damageability
Dynamics of DNA methylation
Establishment of DNA methylation
Maintenance of DNA methylation patterns
Active DNA demethylation
DNA repair factors and DNA methylation
DNA methylation upon DNA repair
References
Chapter 2: DNA damage and histone modifications
Introduction
Histone modifications in DNA double-stranded break repair
Phosphorylation
Phosphorylation on histone H2A.X at serine 139-gH2A.X
Other phosphorylation on histone H2A.X
Phosphorylation on other histones
Ubiquitination
Ubiquitination of histone H2A/H2A.X
Ubiquitination on other histones
Methylation
Methylation of histone H4
Methylation of histone H3
Acetylation
Acetylation of histone H3
Acetylation of histone H4
Histone modifications in DNA excision repair
Histone modifications in DNA mismatch repair
Concluding remarks
References
Chapter 3: DNA damage and histone variants
Introduction
DDR mechanisms
Histone variants
Role of histone variants in DDR
Conclusions
References
Chapter 4: DNA damage and miRNAs
MicroRNA biogenesis and maturation
Effects of DDR on miRNA biogenesis
miRNAs and double-strand break (DSB) repair
miRNAs and homologous recombination (HR) repair
miRNAs and nonhomologous end-joining (NHEJ) repair
miRNAs and base excision repair (BER)
miRNAs and nucleotide excision repair (NER)
miRNAs DNA mismatch repair (MMR)
Role of miRNAs in cell cycle arrest and apoptosis
DDR, miRNAs, and cancer development and treatment
References
Chapter 5: DNA damage and lncRNAs
Introduction
lncRNAs and their biogenesis
lncRNAs and DNA damage
lncRNAs in ATM and ATR pathway
lncRNA in p53 regulatory network
lncRNAs in other signaling pathways
lncRNAs and DNA repair
The role of lncRNAs in the DDR regulation
Conclusion
References
Chapter 6: DNA damage, sirtuins, and epigenetic marks
Sirtuins
Sirtuins and chromatin remodeling
Sirtuins and epigenetic modifications
Histone acetylation and deacetylation
Histone methylation
Sirtuins and telomere maintenance
Sirtuins and genomic stability
Sirtuins and diseases
Concluding remarks
References
Section 2: DNA damage and epigenetics-Their impact in the onset of diseases
Chapter 7: DNA damage, metabolism, and epigenetic regulation
Introduction
The interplay between epigenetics and metabolism
Metabolic dysfunction and DNA repair
Crosstalk between epigenetics and metabolism in cancer
DNA damage
Role of epigenetic alterations in cellular metabolism
Histone methylation
DNA methylation
Histone acetylation
Role of metabolic dysfunction in the context of epigenetics
Metabolic regulation of 2-oxoglutarate-dependent dioxygenases
Metabolic regulation of acetylation
Hexosamine biosynthetic pathway
Phosphopentose pathway
Glycolytic pathway
Metabolic dysfunction, epigenetic modification, and genomic instability
Epigenetics and steroid hormone metabolism in endocrine-driven cancer
Epigenetic alterations in prostate cancer progression
Epigenetic alterations in breast cancer progression
Conclusions and perspectives
Acknowledgments
References
Chapter 8: DNA damage, epigenetics, and aging
Introduction
Epigenetic modifications versus DNA damage
DNA damage causes cellular senescence and aging
Epigenetic marks that prevent DNA damage and aging: Youth-associated genome-stabilizing epigenetic marks
How epigenetic modifications prevent DNA damage and the aging process: DNA Protection vs. DNA repair
IRS hypomethylation drives the molecular pathogenesis of age-related noncommunicable diseases
What are an IRS, the structure of each IRS element, and the distribution of methylation marks in the genome?
IRS methylation levels and pattern changes in human diseases
Mechanisms of IRS hypomethylation and hypermethylation
Mechanisms of IRS methylation and hypermethylation
Mechanisms of IRS hypomethylation
Mechanisms of IRS hypomethylation that drive aging
Loss of DNA protection
LINE-1 activation in late cellular senescence
Other mechanisms of IRS hypomethylation-driven phenotypes
Retrotransposition and retrotransposon protein production
mRNA levels of host genes and mechanisms
IRSs as sources of endogenous siRNAs
Notable roles of IRSs
Youth-DNA-GAPs
The fountain of youth
References
Chapter 9: DNA damage signaling, cell reprogramming, and differentiation
Introduction
DNA damage signaling in cell reprogramming and differentiation
iPS cells derived from DNA repair-deficient disease
Ataxia telangiectasia (A-T)
ATR-Seckel syndrome (ATR-SS)
Fanconi anemia
Nijmegen breakage syndrome (NBS)
NHEJ factors (DNA-PKcs, LIG IV, and Artemis)
Conclusion
References
Chapter 10: The interplay between DNA damage and epigenetics in cancer
Introduction
Genetic factors
Environmental exposures
The cancer epigenome and DNA damage
DNA methylation
Histone modifications
Noncoding RNAs
Chromatin remodelers
Higher order chromatin structure
Susceptibility of the cancer epigenome to DNA damage
Targeting DNA damage and epigenetic changes in cancer diagnosis and treatment
Conclusion
References
Chapter 11: Oncometabolites, epigenetic marks, and DNA repair
Oncometabolite biology
Bridging two hallmarks: Altered metabolism and genomic instability
Oncometabolites identification in cancer
Oncometabolites induce global histone and DNA hypermethylation via αKG-dependent dioxygenase inhibition
Oncometabolites and DNA repair
Early implications of oncometabolites in DNA damage repair
Identification of the oncometabolite-induced HDR deficiency
Oncometabolites disrupt HDR signaling via H3K9 hypermethylation
Therapeutic strategies targeting the oncometabolite-induced HDR defect
References
Section 3: Therapeutic strategies inducing DNA damage and epigenetic alterations
Chapter 12: Cancer therapies inducing DNA damage
Introduction
Mechanisms of DNA damage by radiotherapy
Use of radiotherapy to treat cancer
Conventional radiotherapy
Proton radiotherapy
FLASH radiotherapy
High LET particles in cancer therapy
DNA damage-inducing chemotherapies
Alkylating agents
History
Mechanisms of action
Clinical use
Platinum-based compounds
Discovery
Mechanism of action
Direct actions
Indirect actions
Cisplatin analogs
Clinical use
Antimetabolites
Topoisomerase poisons
Conclusions
Acknowledgments
References
Chapter 13: Epigenetic therapy and DNA damage response
Introduction
Commonly altered epigenetic regulatory proteins implicated in cancer and their implication for therapy
Therapies for aberrant DNA methylation
DNMT inhibition in combination with drugs that target DNA repair pathways
Inhibitors of histone modifications
Lysine methyltransferase inhibitors
Histone deacetylase inhibitors
Inhibitors of histone modifications in combination with drugs that target DNA repair pathways
Targeting epigenetic readers
Targeting the epigenetics of the DNA damage response in cancer: The concept of synthetic lethality
Epigenetic inhibitors in combination with chemotherapy and radiotherapy: Synthetic lethal interactions and clinical applica ...
Implications of epigenetic regulation for radiation treatment
Epigenetic changes of DNA damage repair genes as predictive markers of response to chemotherapy
Epigenetic inhibitors in combination with drugs that target DNA repair components for synthetic lethal therapy
Synthetic lethality induced by SETD2 deficiency and WEE1 inhibition
Synthetic lethality induced by epigenetic aberrations and PARP inhibition
Synthetic lethality induced by SWI/SNF complex mutations and EZH2 inhibition
Conclusion: Implications of epigenetic regulation for improved cancer treatment
References
Section 4: Experimental approaches to study DNA damage and epigenetic modifications
Chapter 14: Useful protocols to study DNA damage
Introduction
Alkaline comet assay
Before you begin
Materials and equipment
Step-by-step method details
Sample collection
Cell lysis
Electrophoresis and neutralization
Fixation and imaging
Expected outcomes
Quantification and statistical analysis
Advantages
Limitations
Optimization and troubleshooting
Safety considerations and standards
Alternative methods/procedures
Enzyme treatment
DNA lesions immunodetection
Immunofluorescence (IF) to detect phosphorylated histone H2AX (Ser139)
Before you begin
Materials and equipment
Step-by-step method details
Sample collection and fixation
Blocking and staining
Mount slides
Imaging
Analysis
Advantages
Limitations
Optimization and troubleshooting
Optimization
Safety considerations and standards
Alternative methods/procedures
Immuno-slot-blot assay for pyrimidine dimers
Before you begin
Buffers needed for rapid extraction of genomic DNA protocol
Materials and equipment
Step-by-step method details
DNA extraction
Optional steps: (rapid genomic DNA extraction)
Sample preparation
Membrane preparation and assemble the slot-blot manifold
Blocking and antibody incubation
Analysis
Expected outcomes
Quantification and statistical analysis
Advantages
Limitations
Optimization and troubleshooting
Optimization
Safety considerations and standards
Alternative methods/procedures
Final remarks
Acknowledgments
References
Chapter 15: Useful methods to study epigenetic marks: DNA methylation, histone modifications, chromatin structure, and no ...
Introduction
Methods used to study DNA methylation
Based on bisulfite treatment
DNA bisulfite treatment
Bisulfite treatment followed by sequence-specific DNA methylation analyses
Whole-genome bisulfite sequencing (WGBS)
Sequencing of reduced representation bisulfite (RRBS)
Enhanced reduced representation bisulfite sequencing (ERRBS)
Hybridization-based microarrays
Based on CpG capture
Methylated DNA immunoprecipitation (MeDIP)
Methyl-CpG binding domain protein sequencing (MBD-seq)
5mC content
High-performance liquid chromatography (HPLC)
Methods used to study histone modifications
Chromatin immunoprecipitation (ChIP)
Immunodetection with specific antibodies
Proteomics
Mass spectrometry (MS)
Methods used to study chromatin accessibility
Deoxyribonuclease treatment followed by DNA sequencing (DNase-seq)
Formaldehyde-assisted isolation of regulatory elements followed by sequencing (FAIRE-seq)
Micrococcal nuclease treatment followed by DNA sequencing (MNase-seq)
Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq)
Methods used to identify chromatin-associated proteins
Chromatin enrichment for proteomics (ChEP)
Methods used to study noncoding RNAs (ncRNA)
ncRNA gene expression analysis
RT-qPCR
RNA sequencing (RNA-seq)
miRNA microarray
miRNA-mediated posttranscriptional regulation analysis
Luciferase assay
Noncoding RNA-protein interactions
RNA immunoprecipitation (RIP)
CrossLinking ImmunoPrecipitation (CLIP)
PhotoActivatable Ribonucleoside enhanced CrossLinking and ImmunoPrecipitation (PAR-CLIP)
LncRNA and chromatin interaction
Chromatin isolation by RNA quantification (ChIRP)
Capture hybridization analysis of RNA targets (CHART)
ncRNA localization
RNA fluorescent in situ hybridization (RNA-FISH)
ncRNA gene expression modulation methods
Downregulation of gene expression
RNA interference (RNAi) for lncRNA knockdown
Antisense oligonucleotides (ASOs) for lncRNA silencing
miRNA inhibitors
Overexpression of ncRNAs
miRNA mimics
CRISPR genome edition
CRISPR gene knockout
CRISPR inhibition (CRISPRi)
CRISPR overexpression by homology-directed repair (HDR)
CRISPR gene activation (CRISPRa)
Conclusions
References
Index
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