Epigenetic regulation of genomic integrity

Deem, Angela K.; Li, Xuan; Tyler, Jessica K.

doi:10.1007/s00412-011-0358-1

Cited by 45 publications

(38 citation statements)

References 204 publications

(283 reference statements)

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“…Recent studies have revealed that K63Ub synthesis is regulated by the deubiquitinating enzyme, OTUB1 (OTU domain-containing ubiquitin aldehyde-binding protein 1; Wiener et al, 2012). It is thought that RNF8 executed ubiquitination has a role in maintaining genomic integrity, however, the role of post-damage monoubiquitylation in chromatin reassembly needs to be elucidated (Deem et al, 2012). It has been reported that RNF8 is inactive toward nucleosomal histone H2A.…”

Section: Histone Ubiquitinationmentioning

confidence: 99%

“…In addition to histones, non-histone proteins are also involved in developing special chromatin structures. The known histone modifications induced following ionizing radiation exposure are phosphorylation, acetylation, methylation, and ubiquitination (Pandita and Richardson, 2009;Deem et al, 2012). Among these major chromatin modifications, post-damage-induced histone phosphorylation has been the most thoroughly studied.…”

Section: Introductionmentioning

confidence: 99%

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Chromatin modifications and the DNA damage response to ionizing radiation

Kumar¹,

Horikoshi²,

Singh³

et al. 2013

Front. Oncol.

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In order to survive, cells have evolved highly effective repair mechanisms to deal with the potentially lethal DNA damage produced by exposure to endogenous as well as exogenous agents. Ionizing radiation exposure induces highly lethal DNA damage, especially DNA double-strand breaks (DSBs), that is sensed by the cellular machinery and then subsequently repaired by either of two different DSB repair mechanisms: (1) non-homologous end joining, which re-ligates the broken ends of the DNA and (2) homologous recombination, that employs an undamaged identical DNA sequence as a template, to maintain the fidelity of DNA repair. Repair of DSBs must occur within the natural context of the cellular DNA which, along with specific proteins, is organized to form chromatin, the overall structure of which can impede DNA damage site access by repair proteins. The chromatin complex is a dynamic structure and is known to change as required for ongoing cellular processes such as gene transcription or DNA replication. Similarly, during the process of DNA damage sensing and repair, chromatin needs to undergo several changes in order to facilitate accessibility of the repair machinery. Cells utilize several factors to modify the chromatin in order to locally open up the structure to reveal the underlying DNA sequence but post-translational modification of the histone components is one of the primary mechanisms. In this review, we will summarize chromatin modifications by the respective chromatin modifying factors that occur during the DNA damage response.

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Section: Histone Ubiquitinationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chromatin modifications and the DNA damage response to ionizing radiation

Kumar¹,

Horikoshi²,

Singh³

et al. 2013

Front. Oncol.

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“…The relaxed chromatin structure facilitates the activation and recruitment of the kinase ATM, which initiates a signaling cascade leading to histone acetylation and additional chromatin remodeling. These modifications at the DSB site promote amplification of the DDR, recruit repair factors, and provide accessibility to the repair machinery (Deem et al 2012). Following repair, acetylation of lysine 56 on histone H3 is required to inactivate the DDR (Chen and Tyler 2008) and to allow reassembly of nucleosomes at the repair site.…”

mentioning

confidence: 99%

X Chromosome Crossover Formation and Genome Stability inCaenorhabditis elegansAre Independently Regulated byxnd-1

McClendon

Rana

Amrit

et al. 2016

G3 Genes|Genomes|Genetics

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The germ line efficiently combats numerous genotoxic insults to ensure the high fidelity propagation of unaltered genomic information across generations. Yet, germ cells in most metazoans also intentionally create double-strand breaks (DSBs) to promote DNA exchange between parental chromosomes, a process known as crossing over. Homologous recombination is employed in the repair of both genotoxic lesions and programmed DSBs, and many of the core DNA repair proteins function in both processes. In addition, DNA repair efficiency and crossover (CO) distribution are both influenced by local and global differences in chromatin structure, yet the interplay between chromatin structure, genome integrity, and meiotic fidelity is still poorly understood. We have used the xnd-1 mutant of Caenorhabditis elegans to explore the relationship between genome integrity and crossover formation. Known for its role in ensuring X chromosome CO formation and germ line development, we show that xnd-1 also regulates genome stability. xnd-1 mutants exhibited a mortal germ line, high embryonic lethality, high incidence of males, and sensitivity to ionizing radiation. We discovered that a hypomorphic allele of mys-1 suppressed these genome instability phenotypes of xnd-1, but did not suppress the CO defects, suggesting it serves as a separation-of-function allele. mys-1 encodes a histone acetyltransferase, whose homolog Tip60 acetylates H2AK5, a histone mark associated with transcriptional activation that is increased in xnd-1 mutant germ lines, raising the possibility that thresholds of H2AK5ac may differentially influence distinct germ line repair events. We also show that xnd-1 regulated him-5 transcriptionally, independently of mys-1, and that ectopic expression of him-5 suppressed the CO defects of xnd-1. Our work provides xnd-1 as a model in which to study the link between chromatin factors, gene expression, and genome stability.

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“…In response to changing conditions during development or in the environment, post-translational protein modification can much more rapidly alter the activity of the proteome compared to transcriptional or translational control mechanisms 4,14,19-21 . While numerous protein modifications are known, for example histone methylation and acetylation, the most widely studied modification is phosphorylation.…”

Section: Introductionmentioning

confidence: 99%

“…Modified-protein-specific antibodies can be used in high-throughput RNAi screens 41 or to test hypotheses related to control of a signaling pathway or utilization of the phosphorylated protein 42-45 . Importantly, modified-protein-specific antibodies can be used to purify protein-protein, protein-DNA or protein-RNA complexes that contain the modified protein; a widely employed example is the use of antibodies specific to modified histones for analysis of genomic regions that contain the modified histone in chromatin 4,14,20,24,46,47 .…”

Section: Introductionmentioning

confidence: 99%

Generation and purification of highly specific antibodies for detecting post-translationally modified proteins in vivo

Arur

Schedl

2014

Nat Protoc

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Post-translational modifications alter protein structure, affecting activity, stability, localization and/or binding partners. Antibodies that specifically recognize post-translationally modified proteins have a number of uses including immuno-cytochemistry and immuno-precipitation of the modified protein to purify protein-protein and protein-nucleic acid complexes. However, antibodies directed at modified sites on individual proteins are often non-specific. Here we describe a protocol to purify polyclonal antibodies that specifically detect the modified protein of interest. The approach uses iterative rounds of subtraction and affinity purification, using stringent washes to remove antibodies that recognize the unmodified protein and low sequence complexity epitopes containing the modified amino acid. Dot and western blots assays are employed to assess antibody preparation specificity. The approach is designed to overcome the common occurrence that a single round of subtraction and affinity purification is not sufficient to obtain a modified protein specific antibody preparation. One full round of antibody purification and specificity testing takes 6 days of discontinuous time.

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Epigenetic regulation of genomic integrity

Cited by 45 publications

References 204 publications

Chromatin modifications and the DNA damage response to ionizing radiation

Chromatin modifications and the DNA damage response to ionizing radiation

X Chromosome Crossover Formation and Genome Stability inCaenorhabditis elegansAre Independently Regulated byxnd-1

Generation and purification of highly specific antibodies for detecting post-translationally modified proteins in vivo

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