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Accurate maintenance of genomic as well as epigenomic integrity is critical for proper cell and organ function. Continuous exposure to DNA damage is, thus, often associated with malignant transformation and degenerative diseases. A significant, chronic threat to genome integrity lies in the process of transcription, which can result in the formation of potentially harmful RNA : DNA hybrid structures (R-loops) and has been linked to DNA damage accumulation as well as dynamic chromatin reorganization. In sharp contrast, recent evidence suggests that active transcription, the resulting transcripts as well as R-loop formation can play multi-faceted roles in maintaining and restoring genome integrity. Here, we will discuss the emerging contributions of transcription as both a source of DNA damage and a mediator of DNA repair. We propose that both aspects have significant implications for genome maintenance, and will speculate on possible long-term consequences for the epigenetic integrity of transcribing cells. This article is part of the themed issue ‘Chromatin modifiers and remodellers in DNA repair and signalling’.

All organisms must safeguard the integrity of their DNA to avoid deleterious consequences of genome instability, which have been linked to human diseases such as autoimmune disorders, neurodegenerative diseases and cancer. Traditionally, genome maintenance has been viewed largely in terms of DNA–protein interactions. However, emerging evidence points to RNA as a key modulator of genome stability, with seemingly opposing roles in promoting chromosomal instability and protecting genome integrity. Unravelling the mechanistic and contextual basis of this duality will not only improve our understanding of the interfaces between RNA and the genome but will also provide important insights into how disrupted RNA metabolism contributes to disease origin, laying the foundation for targeted intervention.Genome instability can lead to a number of human diseases, including neurodegeneration and cancer. In this Review, Zong et al. discuss the various ways in which RNA can both promote genome instability and contribute to genome maintenance.

Tumor growth relies on efficient DNA repair to mitigate the detrimental impact of DNA damage associated with excessive cell division. Modulating repair factor function, thus, provides a promising strategy to manipulate malignant growth. Here, we identify the ubiquitin-specific protease USP21 as a positive regulator of BRCA2, a key mediator of DNA repair by homologous recombination. USP21 interacts with, deubiquitinates and stabilizes BRCA2 to promote efficient RAD51 loading at DNA double-strand breaks. As a result, depletion of USP21 decreases homologous recombination efficiency, causes an increase in DNA damage load and impairs tumor cell survival. Importantly, BRCA2 overexpression partially restores the USP21-associated survival defect. Moreover, we show that USP21 is overexpressed in hepatocellular carcinoma, where it promotes BRCA2 stability and inversely correlates with patient survival. Together, our findings identify deubiquitination as a means to regulate BRCA2 function and point to USP21 as a potential therapeutic target in BRCA2-proficient tumors. BRCA2 is essential for the repair of DNA damage; therefore, defects in BRCA2 are associated with tumorigenesis but also with increased susceptibility to genotoxic stress. Here the authors show that USP21 regulates the ability of tumor cells to repair damaged DNA by regulating BRCA2 stability.

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 identified a protective role for the ATRX-interacting macroH2A1.2 histone variant during homologous recombination 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 DNA double-strand break (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 homologous recombination-associated ALT pathways. Our findings thus identify the dynamic exchange of macroH2A1.2 on chromatin as an epigenetic link among ATRX loss, RS-induced DDR initiation and telomere maintenance via homologous recombination.Histone variant macroH2A1.2 and chromatin remodeler ATRX act jointly to maintain telomere integrity under conditions of acute replication stress in ALT-positive cancer cells.

DNA transactions introduce torsional constraints that pose an inherent risk to genome integrity. While topoisomerase 1 (TOP1) activity is essential for DNA supercoil removal, the aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs) can result in cytotoxic DNA lesions. What protects genomic hot spots of topological stress from excessive TOP1cc accumulation remains unknown. Here, we identify chromatin context as an essential means to coordinate TOP1cc resolution. Through its ability to bind poly(ADP-ribose) (PAR), the histone variant macroH2A1.1 facilitates TOP1cc repair factor recruitment and lesion turnover, thereby preventing DNA damage in response to transcription-associated topological stress. The alternatively spliced macroH2A1.2 isoform is unable to bind PAR or protect from TOP1ccs. Impaired macroH2A1.1 splicing, a frequent cancer feature, was predictive of increased sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect. We propose macroH2A1 alternative splicing as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability. DNA transactions promote torsional constraints that pose inherent risks to genome integrity. Here the authors identify the macro-histone splice variant macroH2A1.1 as an epigenetic modulator of topoisomerase 1-associated genome maintenance. MacroH2A1.1 expression determines sensitivity to TOP1 poisons and may present a cancer vulnerability.

Numerous longevity genes have been discovered in model organisms and altering their function results in prolonged lifespan. In mammals, some have speculated that any health benefits derived from manipulating these same pathways might be offset by increased cancer risk on account of their propensity to boost cell survival. The Sir2/SIRT1 family of NAD(+)-dependent deacetylases is proposed to underlie the health benefits of calorie restriction (CR), a diet that broadly suppresses cancer in mammals. Here we show that CR induces a two-fold increase SIRT1 expression in the intestine of rodents and that ectopic induction of SIRT1 in a beta-catenin-driven mouse model of colon cancer significantly reduces tumor formation, proliferation, and animal morbidity in the absence of CR. We show that SIRT1 deacetylates beta-catenin and suppresses its ability to activate transcription and drive cell proliferation. Moreover, SIRT1 promotes cytoplasmic localization of the otherwise nuclear-localized oncogenic form of beta-catenin. Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of beta-catenin in 81 human colon tumor specimens analyzed. Taken together, these observations show that SIRT1 suppresses intestinal tumor formation in vivo and raise the prospect that therapies targeting SIRT1 may be of clinical use in beta-catenin-driven malignancies.

Alternative splicing of pre-messenger RNA is a key feature of transcriptome expansion in eukaryotic cells, yet its regulation is poorly understood. Spliceosome assembly occurs co-transcriptionally, raising the possibility that DNA structure may directly influence alternative splicing. Supporting such an association, recent reports have identified distinct histone methylation patterns, elevated nucleosome occupancy and enriched DNA methylation at exons relative to introns. Moreover, the rate of transcription elongation has been linked to alternative splicing. Here we provide the first evidence that a DNA-binding protein, CCCTC-binding factor (CTCF), can promote inclusion of weak upstream exons by mediating local RNA polymerase II pausing both in a mammalian model system for alternative splicing, CD45, and genome-wide. We further show that CTCF binding to CD45 exon 5 is inhibited by DNA methylation, leading to reciprocal effects on exon 5 inclusion. These findings provide a mechanistic basis for developmental regulation of splicing outcome through heritable epigenetic marks.

Accurate maintenance of genomic as well as epigenomic integrity is critical for proper cell and organ function. Continuous exposure to DNA damage is, thus, often associated with malignant transformation and degenerative diseases. A significant, chronic threat to genome integrity lies in the process of transcription, which can result in the formation of potentially harmful RNA: DNA hybrid structures (R-loops) and has been linked to DNA damage accumulation as well as dynamic chromatin reorganization. In sharp contrast, recent evidence suggests that active transcription, the resulting transcripts as well as R-loop formation can play multifaceted roles in maintaining and restoring genome integrity. Here, we will discuss the emerging contributions of transcription as both a source of DNA damage and a mediator of DNA repair. We propose that both aspects have significant implications for genome maintenance, and will speculate on possible long-term consequences for the epigenetic integrity of transcribing cells. This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'.