Epigenome Maintenance in Response to DNA Damage

Speaker:     Sophie Polo (University Paris Diderot)
Subject:      New insights into epigenome maintenance in response to DNA damage by real-time tracking of histone dynamics in human cells
Location:    Erasmus MC Rotterdam
Date:           Wednesday, 15.06.2015

Author: Edgar Schönfeld

The epigenome comprises a set of chemical modifications of the chromatin that regulate gene expression. It manifests itself in phenomena such as DNA methylations, histone modifications, and changes in chromatin folding. The epigenome can be passed to the next generation, although it changes dynamically over time. Sophie Polo’s work focusses on the preservation of epigenetic information that is encoded in histone modifications.
Histones enable the tight packaging of DNA in eukaryotic cells. A DNA strand is wound around octameric histone complexes and fixed via linker histones (This is called nucleosome). However, histones form a barrier to DNA repair. In order to access damaged DNA sequences, the appertaining histones first have to be removed or disassembled and subsequently be restored. This is generally referred to as ‘Access-Repair-Restore’ model. The question is whether the original histones or new histones are reincorporated after the repair has taken place. In the latter case, it is unclear if or how histone modifications are conserved.

ARR
Acces-Repair-Restore Model [1]

In order to maintain a stable epigenetic signature over time, epigenetic marks have to be faithfully restored after each DNA repair event. That includes the histone variant composition of a nucleosome, as well as its post-translational modifications. Already in 2006 Polo and colleagues observed that a certain histone variant, histone H3.1, is incorporated as newly synthesized substrate after nucleotide excision repair, following UV-induced damage. The deposition is mediated by the histone chaperone chromatin assembly factor 1 (CAF-1). This finding posed a challenge to epigenetic memory. There are two theories concerning the conservation of epigenetic information of removed histones: First of all, it could be the case that parental histone marks are transferred to the newly incorporated histones according to similar principles that apply to the inheritance of epigenetic marks in the process of replication. Secondly, it might be that no epigenetic information is transferred and the new histones serve as damage scars. These marks could be part of an adaption mechanism against further damage infliction. Polo went on to examine the link between DNA repair and histone removal and restoration. It was found that some other histone variants are replaced as well, while most histones just diffuse away during DNA repair and subsequently return to their original site. In particular, Polo said that 90% of the parental histones are conserved, which is good news for epigenetic integrity.
At this point of time, one can already say that Polo’s work has created important insights into epigenetic maintenance and I would not be surprised if her findings are incorporated in future textbooks.

[1] Polo SE, Roche D, Almouzni G. New histone incorporation marks sites of UV repair in human cells. Cell. 2006 Nov 3;127(3):481-93.

 

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