Histone H3E73Q and H4E53A mutations cause recombinogenic DNA damage.

Pedro Ortega,Ana G Rondón,Andrés Aguilera,Belén Gómez-González,Marta San Martin-Alonso,Desiré García-Pichardo

doi:10.15698/mic2020.07.723

Pedro Ortega, Ana G Rondón + Show 4 more

Open Access

https://doi.org/10.15698/mic2020.07.723

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Abstract

The stability and function of eukaryotic genomes is closely linked to histones and to chromatin structure. The state of the chromatin not only affects the probability of DNA to undergo damage but also DNA repair. DNA damage can result in genetic alterations and subsequent development of cancer and other genetic diseases. Here, we identified two mutations in conserved residues of histone H3 and histone H4 (H3E73Q and H4E53A) that increase recombinogenic DNA damage. Our results suggest that the accumulation of DNA damage in these histone mutants is largely independent on transcription and might arise as a consequence of problems occurring during DNA replication. This study uncovers the relevance of H3E73 and H4E53 residues in the protection of genome integrity.

Highlights

Genetic instability is prevented through multiple processes to avoid cell death and tumorigenesis
Accumulated evidence supports that most genetic instability sources arise from unrepaired DNA damage, such as double strand breaks (DSBs), or failures during DNA replication that can lead to breaks
Chromatin can play an active role in regulating DNA repair, as first exemplified by the phosphorylation of the serine 189 of mammalian H2AX histone variant, one of the earliest signals of the DNA damage checkpoint that expands up to 2 Mb around DSBs initiating a cascade of recruitment of repair factors [5]

Summary

Introduction

Genetic instability is prevented through multiple processes to avoid cell death and tumorigenesis. Chromatin can play an active role in regulating DNA repair, as first exemplified by the phosphorylation of the serine 189 of mammalian H2AX histone variant (serine 129 phosphorylation of H2A in yeast, P-H2A), one of the earliest signals of the DNA damage checkpoint that expands up to 2 Mb around DSBs initiating a cascade of recruitment of repair factors [5] Since this modification was discovered, several other histone posttranslational modifications have been described to affect DNA damage repair, including the methylation of lysine and arginine, phosphorylation of serine and threonine and acetylation, ubiquitylation or sumoylation of lysine [6]

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