Dual RNA 3’-end processing of H2A.X messenger RNA maintains DNA damage repair throughout the cell cycle

Esther Griesbach, Margarita Schlackow, William F. Marzluff and Nick J. Proudfoot ()
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Esther Griesbach: University of Oxford, South Parks Road
Margarita Schlackow: University of Oxford, South Parks Road
William F. Marzluff: University of North Carolina
Nick J. Proudfoot: University of Oxford, South Parks Road

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Phosphorylated H2A.X is a critical chromatin marker of DNA damage repair (DDR) in higher eukaryotes. However, H2A.X gene expression remains relatively uncharacterised. Replication-dependent (RD) histone genes generate poly(A)- mRNA encoding new histones to package DNA during replication. In contrast, replication-independent (RI) histone genes synthesise poly(A)+ mRNA throughout the cell cycle, translated into histone variants that confer specific epigenetic patterns on chromatin. Remarkably H2AFX, encoding H2A.X, is a hybrid histone gene, generating both poly(A)+ and poly(A)- mRNA isoforms. Here we report that the selective removal of either mRNA isoform reveals different effects in different cell types. In some cells, RD H2A.X poly(A)- mRNA generates sufficient histone for deposition onto DDR associated chromatin. In contrast, cells making predominantly poly(A)+ mRNA require this isoform for de novo H2A.X synthesis, required for efficient DDR. This highlights the importance of differential H2A.X mRNA 3’-end processing in the maintenance of effective DDR.

Date: 2021
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DOI: 10.1038/s41467-020-20520-6

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