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Regulation of the supply and proper localization of histones, the cornerstones of genome integrity

The team of Genevieve Almouzni, director of the research unit "Nuclear Dynamics and Genome Plasticity"  (Institut Curie/UMR218 CNRS), shows in two papers published in Molecular Cell how the cells make proper use of histones.
To understand the importance of these discoveries, we must return to the function of histones ... These are essential building blocks that promote the spatial organization and compaction of the genetic material into chromatin in the cell nucleus. But beyond the mere compaction of about 2 meters of DNA within a nucleus of about 5 microns in diameter, this organization provides additional information to that of the genetic code. The importance of histones is at the heart of current research in the field of epigenetics, a new discipline at the frontiers of genetics.

HIGHLIGHTS

Centromeres are essential for ensuring proper chromosome segregation in eukaryotes. Their definition relies on the presence of a centromere-specific H3 histone variant CenH3, known as CENP-A in mammals. Its overexpression in aggressive cancers raises questions concerning its effect on chromatin dynamics and contribution to tumorigenesis. We find that CenH3 overexpression in human cells leads to ectopic enrichment at sites of active histone turnover involving a heterotypic tetramer containing CenH3-H4 with H3.3-H4. Ectopic localization of this particle depends on the H3.3 chaperone DAXX rather than the dedicated CenH3 chaperone HJURP. This aberrant nucleosome occludes CTCF binding and has a minor effect on gene expression. Cells overexpressing CenH3 are more tolerant of DNA damage. Both the survival advantage and CTCF occlusion in these cells are dependent on DAXX. Our findings illustrate how changes in histone variant levels can disrupt chromatin dynamics and suggests a possible mechanism for cell resistance to anticancer treatments.

Understanding how to recover fully functional and transcriptionally active chromatin when its integrity has been challenged by genotoxic stress is a critical issue. Here, by investigating how chromatin dynamics regulate transcriptional activity in response to DNA damage in human cells, we identify a pathway involving the histone chaperone histone regulator A (HIRA) to promote transcription restart after UVC damage. Our mechanistic studies reveal that HIRA accumulates at sites of UVC irradiation upon detection of DNA damage prior to repair and deposits newly synthesized H3.3 histones. This local action of HIRA depends on ubiquitylation events associated with damage recognition. Furthermore, we demonstrate that the early and transient function of HIRA in response to DNA damage primes chromatin for later reactivation of transcription. We propose that HIRA-dependent histone deposition serves as a chromatin bookmarking system to facilitate transcription recovery after genotoxic stress.

 

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Presentation from David Gentien about the genomic platform of the Institut Curie

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