Lee Tae-Hee, Qiao Colina X, Kuzin Vladislav, Shi Yuepeng, Farkas Marina, Zhao Zhiyan, Ramanarayanan Vijayalalitha, Wu Tongyu, Guan Tianyi, Zhou Xianzhen, Corujo David, Buschbeck Marcus, Baranello Laura, Oberdoerffer Philipp
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Nat Commun. 2025 Aug 12;16(1):7458. doi: 10.1038/s41467-025-62598-w.
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 交易引入了扭转约束，这对基因组完整性构成了内在风险。虽然拓扑异构酶 1（TOP1）的活性对于去除 DNA 超螺旋至关重要，但 TOP1：DNA 裂解复合物（TOP1ccs）的异常稳定会导致细胞毒性 DNA 损伤。什么能保护拓扑应力的基因组热点免受过度的 TOP1cc 积累尚不清楚。在这里，我们确定染色质环境是协调 TOP1cc 解决的重要手段。通过其结合聚（ADP - 核糖）（PAR）的能力，组蛋白变体 macroH2A1.1 促进了 TOP1cc 修复因子的募集和损伤周转，从而防止了响应转录相关拓扑应力时的 DNA 损伤。可变剪接的 macroH2A1.2 异构体无法结合 PAR 或保护免受 TOP1ccs 的影响。macroH2A1.1 剪接受损是一种常见的癌症特征，在乳腺癌细胞的药物基因组筛选中可预测对 TOP1 毒物的敏感性增加，并且 macroH2A1.1 失活反映了这种效应。我们提出 macroH2A1 可变剪接作为 TOP1 相关基因组维持的表观遗传调节剂和潜在的癌症脆弱点。
