Epigenetic Regulation of DNA Repair Pathway Choice by MacroH2A1 Splice Variants Ensures Genome Stability
The inactive X chromosome (Xi) is inherently susceptible to genomic aberrations. Replication stress (RS) has been proposed as an underlying cause, but the mechanisms that protect from Xi instability remain unknown. Here, we show that macroH2A1.2, an RS-protective histone variant enriched on the Xi,...
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Veröffentlicht in: | Molecular cell 2020-09, Vol.79 (5), p.836-845.e7 |
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Zusammenfassung: | The inactive X chromosome (Xi) is inherently susceptible to genomic aberrations. Replication stress (RS) has been proposed as an underlying cause, but the mechanisms that protect from Xi instability remain unknown. Here, we show that macroH2A1.2, an RS-protective histone variant enriched on the Xi, is required for Xi integrity and female survival. Mechanistically, macroH2A1.2 counteracts its structurally distinct and equally Xi-enriched alternative splice variant, macroH2A1.1. Comparative proteomics identified a role for macroH2A1.1 in alternative end joining (alt-EJ), which accounts for Xi anaphase defects in the absence of macroH2A1.2. Genomic instability was rescued by simultaneous depletion of macroH2A1.1 or alt-EJ factors, and mice deficient for both macroH2A1 variants harbor no overt female defects. Notably, macroH2A1 splice variant imbalance affected alt-EJ capacity also in tumor cells. Together, these findings identify macroH2A1 splicing as a modulator of genome maintenance that ensures Xi integrity and may, more broadly, predict DNA repair outcome in malignant cells.
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•The macroH2A1.2 histone variant promotes Xi stability and female survival in mice•Balanced macroH2A1 splice variant expression ensures genome integrity•MacroH2A1.1 promotes alt-EJ and genome instability in macroH2A1.2 knockout mice•MacroH2A1 splice variants affect DNA repair pathway choice in cancer cells
Sebastian et al. demonstrate that balanced expression of macroH2A1 splice variants is essential to ensure genome integrity. Deletion of macroH2A1.2 in mice results in X chromosome instability through aberrant alternative end joining mediated by macroH2A1.1. MacroH2A1 splice variant imbalance is also predictive of DNA repair outcome in cancer cells. |
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ISSN: | 1097-2765 1097-4164 |
DOI: | 10.1016/j.molcel.2020.06.028 |