Epigenetic Regulation of DNA Repair Pathway Choice by MacroH2A1 Splice Variants Ensures Genome Stability.

Abstract

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.

• Authors: Robin Sebastian, Eri K Hosogane, Eric G Sun, Andy D Tran, William C Reinhold, Sandra Burkett, David M Sturgill, Prabhakar R Gudla, Yves Pommier, Mirit I Aladjem, Philipp Oberdoerffer
• Journal: Molecular cell (Mol Cell) Vol. 79 Issue 5 Pg. 836-845.e7 (09 03 2020) ISSN: 1097-4164 [Electronic] United States
• PMID: 32649884 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• Histones
• Macroh2a1 protein, mouse

Topics

• Alternative Splicing
• Anaphase
• Animals
• Cell Line
• Chromosomal Instability
• Chromosomes, Human, X
• DNA Repair
• Epigenesis, Genetic
• Female
• Genomic Instability
• Histones (genetics, physiology)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout