SUMMARY
Appropriate DNA double-strand break (DSB) repair factor choice is essential for ensuring accurate repair outcome and genomic integrity. The factors that regulate this process remain poorly understood. Here, we identify two repressive chromatin components, the macrohistone variant macroH2A1 and the H3K9 methyltransferase and tumor suppressor PRDM2, which together direct the choice between the antagonistic DSB repair mediators BRCA1 and 53BP1. The macroH2A1/PRDM2 module mediates an unexpected shift from accessible to condensed chromatin that requires the ataxia telangiectasia mutated (ATM)-dependent accumulation of both proteins at DSBs in order to promote DSB-flanking H3K9 dimethylation. Remarkably, loss of macroH2A1 or PRDM2, as well as experimentally induced chromatin decondensation, impairs the retention of BRCA1, but not 53BP1, at DSBs. As a result, mac-roH2A1 and/or PRDM2 depletion causes epistatic defects in DSB end resection, homology-directed repair, and the resistance to poly(ADP-ribose) polymerase (PARP) inhibition—all hallmarks of BRCA1-deficient tumors. Together, these findings identify dynamic, DSB-associated chromatin reorganization as a critical modulator of BRCA1-dependent genome maintenance.
Recent integrative epigenome analyses highlight the importance of functionally distinct chromatin states for accurate cell function. How these states are established and maintained is a matter of intense investigation. Here, we present evidence for DNA damage as an unexpected means to shape a protective chromatin environment at regions of recurrent replication stress (RS). Upon aberrant fork stalling, DNA damage signaling and concomitant H2AX phosphorylation coordinate the FACT-dependent deposition of macroH2A1.2, a histone variant that promotes DNA repair by homologous recombination (HR). MacroH2A1.2, in turn, facilitates the accumulation of the tumor suppressor and HR effector BRCA1 at replication forks to protect from RS-induced DNA damage. Consequently, replicating primary cells steadily accrue macroH2A1.2 at fragile regions, whereas macroH2A1.2 loss in these cells triggers DNA damage signaling-dependent senescence, a hallmark of RS. Altogether, our findings demonstrate that recurrent DNA damage contributes to the chromatin landscape to ensure the epigenomic integrity of dividing cells.
DNA double-strand breaks (DSBs) and their repair can cause extensive epigenetic changes. As a result, DSBs have been proposed to promote transcriptional and, ultimately, physiological dysfunction via both cell-intrinsic and cell-non-autonomous pathways. Studying the consequences of DSBs in higher organisms has, however, been hindered by a scarcity of tools for controlled DSB induction. Here, we describe a mouse model that allows for both tissue-specific and temporally controlled DSB formation at ∼140 defined genomic loci. Using this model, we show that DSBs promote a DNA damage signaling-dependent decrease in gene expression in primary cells specifically at break-bearing genes, which is reversed upon DSB repair. Importantly, we demonstrate that restoration of gene expression can occur independently of cell cycle progression, underlining its relevance for normal tissue maintenance. Consistent with this, we observe no evidence for persistent transcriptional repression in response to a multi-day course of continuous DSB formation and repair in mouse lymphocytes in vivo. Together, our findings reveal an unexpected capacity of primary cells to maintain transcriptome integrity in response to DSBs, pointing to a limited role for DNA damage as a mediator of cell-autonomous epigenetic dysfunction.
The maintenance of genomic integrity in response to DNA damage is tightly linked to controlled changes in the damage-proximal chromatin environment. Many of the chromatin modifying enzymes involved in DNA repair depend on metabolic intermediates as cofactors, suggesting that changes in cellular metabolism can have direct consequences for repair efficiency and ultimately, genome stability. Here, we discuss how metabolites may contribute to DNA double-strand break repair, and how alterations in cellular metabolism associated with both aging and tumorigenesis may affect the integrity of our genomes.
The growth of telomerase-deficient cancers depends on the alternative lengthening of telomeres (ALT), a homology-directed telomere maintenance pathway. ALT telomeres exhibit a unique chromatin environment and generally lack the nucleosome remodeler ATRX, pointing to an epigenetic basis for ALT. Recently, we have identified a protective role for the ATRX-interacting macroH2A1.2 histone variant during homologous recombination (HR) and replication stress (RS). Consistent with an inherent susceptibility to RS, we show that human ALT telomeres are highly enriched for macroH2A1.2. However, in contrast to ATRX-proficient cells, ALT telomeres transiently lose macroH2A1.2 during acute RS to facilitate DSB formation, a process that is almost completely prevented by ectopic ATRX expression. Telomeric macroH2A1.2 is re-deposited in a DNA damage response (DDR)-dependent manner to promote HR-associated ALT pathways. Our findings thus identify the dynamic exchange of macroH2A1.2 on chromatin as an epigenetic link between ATRX loss, RS-induced DDR initiation and telomere maintenance via HR.
The macroH2A1.2 histone variant facilitates the response to replication stress with implications for genome maintenance and cell growth. A mutually exclusive splice variant, macroH2A1.1, has opposing effects on DNA repair outcome and proliferation. Here we discuss the potential impact of splicing-modulated macroH2A1 chromatin organization for cell function and malignant transformation.
Alcoholic steatohepatitis (ASH) is a progression hepatitis with severe fatty liver and its mortality rate for 30-days in patients are over 30%. Additionally, ASH is well known for one-fifth all alcoholic related liver diseases in the world. Excessive chronic alcohol consumption is one of the most common causes of the progression of ASH and is associated with poor prognosis and liver failure. Alcohol abuse dysregulates the lipid homeostasis and causes oxidative stress and inflammation in the liver. Consequently, metabolic pathways stimulating hepatic accumulation of excessive lipid droplets are induced. Recently, many studies have indicated a link between ASH and epigenetic changes, showing differential expression of alcohol-induced epigenetic genes in the liver. However, the specific mechanisms underlying the pathogenesis of ASH remain elusive. Thus, we here summarize the current knowledge about the roles of epigenetics in lipogenesis, inflammation, and apoptosis in the context of ASH pathophysiology. Especially, we highlight the latest findings on the roles of Sirtuins, a conserved family of class-III histone deacetylases, in ASH. Additionally, we discuss the involvement of DNA methylation, histone modifications, and miRNAs in ASH as well as the ongoing efforts for the clinical translation of the findings in ASH-related epigenetic changes.
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