Year: 2025
Type: article
Abstract: DNA transactions introduce torsional constraints that pose an inherent risk to genome integrity. While topoisomerase 1 (TOP1) activity is essential for removing DNA supercoiling, aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs) can result in cytotoxic DNA lesions. What protects genomic hot spots of topological stress from aberrant TOP1 activity remains unknown. Here, we identify chromatin context as an essential means to coordinate TOP1cc resolution. Through its ability to bind poly(ADP-ribose) (PAR), a protein modification required for TOP1cc repair, the histone variant macroH2A1.1 establishes a TOP1-permissive chromatin environment, while the alternatively spliced macroH2A1.2 isoform is unable to bind PAR or protect from TOP1ccs. By visualizing transcription-induced topological stress in single cells, we find that macroH2A1.1 facilitates PAR-dependent recruitment of the TOP1cc repair effector XRCC1 to protect from ssDNA damage. 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. Consistent with this, low macroH2A1.1 expression correlated with improved survival in cancer patients treated with TOP1 inhibitors. We propose that macroH2A1 alternative splicing serves as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability.
Source: Nature Communications
Authors: Tae-Hee Lee, Colina X. Qiao, Vladislav Kuzin, Yuepeng Shi, Marina Farkas, Zhiyan Zhao, Vijayalalitha Ramanarayanan, Tongyu Wu, Tianyi Guan, Xianzhen Zhou, David Corujo, Marcus Buschbeck, Laura Baranello, Philipp Oberdoerffer
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Science Foundation, U.S. Department of Health and Human Services, University of Pennsylvania, Johns Hopkins University, Cancerfonden, Ministerio de Economía y Competitividad, Karolinska Institutet, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, National Institutes of Health, European Regional Development Fund, Agencia Estatal de Investigación, Uppsala Multidisciplinary Center for Advanced Computational Science, National Cancer Institute, National Institute of General Medical Sciences
Awards: G1305553894, G1373546608, G142144760, G1622782223, G2249011412, G2262748287, G237047288, G2791487596, G3083716140, G3480869486, Probing the mechanisms that control DNA repair pathway choice., G3833254582, G4256646094, G425668148, G4424090058, G451917667, Epigenetic mechanisms controlling single-stranded DNA lesion sensitivity and mutagenesis, G4913389667, G5419800355, G5967599077, G6774526977, G6832510969, G7084143925, G74440900, G7925185095, G7928666424, NAISS, G9000196955
OpenAlex ID: W4413113648