Preserving genome function and stability are paramount for ensuring cellular homeostasis, an imbalance in which can promote diseases including cancer. In the presence of DNA lesions, cells activate ...pathways referred to as the DNA damage response (DDR). As nuclear DNA is bound by histone proteins and organized into chromatin in eukaryotes, DDR pathways have evolved to sense, signal and repair DNA damage within the chromatin environment. Histone proteins, which constitute the building blocks of chromatin, are highly modified by post-translational modifications (PTMs) that regulate chromatin structure and function. An essential histone PTM involved in the DDR is histone methylation, which is regulated by histone methyltransferase (HMT) and histone demethylase (HDM) enzymes that add and remove methyl groups on lysine and arginine residues within proteins respectively. Methylated histones can alter how proteins interact with chromatin, including their ability to be bound by reader proteins that recognize these PTMs. Here, we review histone methylation in the context of the DDR, focusing on DNA double-strand breaks (DSBs), a particularly toxic lesion that can trigger genome instability and cell death. We provide a comprehensive overview of histone methylation changes that occur in response to DNA damage and how the enzymes and reader proteins of these marks orchestrate the DDR. Finally, as many epigenetic pathways including histone methylation are altered in cancer, we discuss the potential involvement of these pathways in the etiology and treatment of this disease.
Chromatin-based DNA damage response (DDR) pathways are fundamental for preventing genome and epigenome instability, which are prevalent in cancer. Histone acetyltransferases (HATs) and histone ...deacetylases (HDACs) catalyze the addition and removal of acetyl groups on lysine residues, a post-translational modification important for the DDR. Acetylation can alter chromatin structure as well as function by providing binding signals for reader proteins containing acetyl-lysine recognition domains, including the bromodomain (BRD). Acetylation dynamics occur upon DNA damage in part to regulate chromatin and BRD protein interactions that mediate key DDR activities. In cancer, DDR and acetylation pathways are often mutated or abnormally expressed. DNA damaging agents and drugs targeting epigenetic regulators, including HATs, HDACs, and BRD proteins, are used or are being developed to treat cancer. Here, we discuss how histone acetylation pathways, with a focus on acetylation reader proteins, promote genome stability and the DDR. We analyze how acetylation signaling impacts the DDR in the context of cancer and its treatments. Understanding the relationship between epigenetic regulators, the DDR, and chromatin is integral for obtaining a mechanistic understanding of genome and epigenome maintenance pathways, information that can be leveraged for targeting acetylation signaling, and/or the DDR to treat diseases, including cancer.
This meta-analysis, spanning 5 decades of Draw-A-Scientist studies, examined U.S. children's gender-science stereotypes linking science with men. These stereotypes should have weakened over time ...because women's representation in science has risen substantially in the United States, and mass media increasingly depict female scientists. Based on 78 studies (N = 20,860; grades K-12), children's drawings of scientists depicted female scientists more often in later decades, but less often among older children. Children's depictions of scientists therefore have become more gender diverse over time, but children still associate science with men as they grow older. These results may reflect that children observe more male than female scientists in their environments, even though women's representation in science has increased over time.
Upon DNA damage, histone modifications are dynamically reshaped to accommodate DNA damage signaling and repair within chromatin. In this study, we report the identification of the histone demethylase ...KDM5A as a key regulator of the bromodomain protein ZMYND8 and NuRD (nucleosome remodeling and histone deacetylation) complex in the DNA damage response. We observe KDM5A-dependent H3K4me3 demethylation within chromatin near DNA double-strand break (DSB) sites. Mechanistically, demethylation of H3K4me3 is required for ZMYND8-NuRD binding to chromatin and recruitment to DNA damage. Functionally, KDM5A deficiency results in impaired transcriptional silencing and repair of DSBs by homologous recombination. Thus, this study identifies a crucial function for KDM5A in demethylating H3K4 to allow ZMYND8-NuRD to operate within damaged chromatin to repair DSBs.
Histone variants represent chromatin components that diversify the structure and function of the genome. The variants of H2A, primarily H2A.X, H2A.Z and macroH2A, are well-established participants in ...DNA damage response (DDR) pathways, which function to protect the integrity of the genome. Through their deposition, post-translational modifications and unique protein interaction networks, these variants guard DNA from endogenous threats including replication stress and genome fragility as well as from DNA lesions inflicted by exogenous sources. A growing body of work is now providing a clearer picture on the involvement and mechanistic basis of H2A variant contribution to genome integrity. Beyond their well-documented role in gene regulation, we review here how histone H2A variants promote genome stability and how alterations in these pathways contribute to human diseases including cancer.
•Genome integrity relies on diverse histone H2A variants and their modifications.•γH2A.X foci represent 3-D damage signaling frameworks formed by chromatin loops.•macroH2A.1 is a splicing-regulated modulator of DSB repair pathway choice.•H2A.J and H2A.B variants are emerging as effectors of DNA repair.•H2A variant functions including genome integrity are linked with several human pathologies.
Although long overlooked, it is now well understood that DNA does not systematically assemble into a canonical double helix, known as B-DNA, throughout the entire genome but can also accommodate ...other structures including DNA hairpins, G-quadruplexes and RNA:DNA hybrids. Notably, these non-canonical DNA structures form preferentially at transcriptionally active loci. Acting as replication roadblocks and being targeted by multiple machineries, these structures weaken the genome and render it prone to damage, including DNA double-strand breaks (DSB). In addition, secondary structures also further accumulate upon DSB formation. Here we discuss the potential functions of pre-existing or de novo formed nucleic acid structures, as bona fide repair intermediates or repair roadblocks, especially during Transcription-Coupled DNA Double-Strand Break repair (TC-DSBR), and provide an update on the specialized protein complexes displaying the ability to remove these structures to safeguard genome integrity.
Although both homologous recombination (HR) and nonhomologous end joining can repair DNA double-strand breaks (DSBs), the mechanisms by which one of these pathways is chosen over the other remain ...unclear. Here we show that transcriptionally active chromatin is preferentially repaired by HR. Using chromatin immunoprecipitation-sequencing (ChIP-seq) to analyze repair of multiple DSBs induced throughout the human genome, we identify an HR-prone subset of DSBs that recruit the HR protein RAD51, undergo resection and rely on RAD51 for efficient repair. These DSBs are located in actively transcribed genes and are targeted to HR repair via the transcription elongation-associated mark trimethylated histone H3 K36. Concordantly, depletion of SETD2, the main H3 K36 trimethyltransferase, severely impedes HR at such DSBs. Our study thereby demonstrates a primary role in DSB repair of the chromatin context in which a break occurs.
Genetic information is recorded in specific DNA sequences that must be protected to preserve normal cellular function. Genome maintenance pathways have evolved to sense and repair DNA damage. ...Importantly, deleterious mutations that occur from mis-repaired lesions can lead to diseases such as cancer. As eukaryotic DNA is bound by histone proteins and organized into chromatin, the true in vivo substrate of transcription, replication and DNA repair is chromatin. Almost 50 years ago, it was found that histones contained the post-translational modification (PTM), acetylation. With the cloning and identification of transcription associated histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes that write and erase the histone acetylation mark respectively, it was realized that this histone modification could be dynamically regulated. Chromatin is subjected to numerous PTMs that regulate chromatin structure and function, including DNA repair. As different organisms contain different histone modifications, chromatin-associated proteins and chromatin states, it is likely that chromatin-templated processes such as DNA repair will exhibit organismal differences. This article focuses on the DNA damage response (DDR) in mammalian cells and how the concerted activities of HAT and HDAC enzymes, and their histone acetylation targets, specifically participate in DNA double-strand break (DSB) repair. Defects in DNA repair and chromatin pathways are observed in cancer, and these pathways represent cancer therapeutic targets. Therefore, understanding the relationship between DNA repair and histone acetylations is important for providing mechanistic details of DSB repair within chromatin that has the potential to be exploited in the clinic.
The alternative non-homologous end-joining (NHEJ) machinery facilitates several genomic rearrangements, some of which can lead to cellular transformation. This error-prone repair pathway is triggered ...upon telomere de-protection to promote the formation of deleterious chromosome end-to-end fusions. Using next-generation sequencing technology, here we show that repair by alternative NHEJ yields non-TTAGGG nucleotide insertions at fusion breakpoints of dysfunctional telomeres. Investigating the enzymatic activity responsible for the random insertions enabled us to identify polymerase theta (Polθ; encoded by Polq in mice) as a crucial alternative NHEJ factor in mammalian cells. Polq inhibition suppresses alternative NHEJ at dysfunctional telomeres, and hinders chromosomal translocations at non-telomeric loci. In addition, we found that loss of Polq in mice results in increased rates of homology-directed repair, evident by recombination of dysfunctional telomeres and accumulation of RAD51 at double-stranded breaks. Lastly, we show that depletion of Polθ has a synergistic effect on cell survival in the absence of BRCA genes, suggesting that the inhibition of this mutagenic polymerase represents a valid therapeutic avenue for tumours carrying mutations in homology-directed repair genes.
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