Limits...
Chromatin dynamics during nucleotide excision repair: histones on the move.

Adam S, Polo SE - Int J Mol Sci (2012)

Bottom Line: Several decades of analysis combining in vitro and in vivo studies in various model organisms ranging from yeast to human have markedly increased our understanding of the mechanisms underlying chromatin disorganization upon damage detection and re-assembly after repair.We also highlight how these methods have provided key mechanistic insight into histone dynamics coupled to repair in mammals, raising new issues about the maintenance of chromatin integrity.In particular, we discuss how NER factors and central players in chromatin dynamics such as histone modifiers, nucleosome remodeling factors, and histone chaperones function to mobilize histones during repair.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Chromatin Dynamics, Curie Institute Research Centre, 75248 Paris Cedex 5, France; E-Mail: salome.adam@curie.fr ; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 218, 75248 Paris Cedex 5, France.

ABSTRACT
It has been a long-standing question how DNA damage repair proceeds in a nuclear environment where DNA is packaged into chromatin. Several decades of analysis combining in vitro and in vivo studies in various model organisms ranging from yeast to human have markedly increased our understanding of the mechanisms underlying chromatin disorganization upon damage detection and re-assembly after repair. Here, we review the methods that have been developed over the years to delineate chromatin alterations in response to DNA damage by focusing on the well-characterized Nucleotide Excision Repair (NER) pathway. We also highlight how these methods have provided key mechanistic insight into histone dynamics coupled to repair in mammals, raising new issues about the maintenance of chromatin integrity. In particular, we discuss how NER factors and central players in chromatin dynamics such as histone modifiers, nucleosome remodeling factors, and histone chaperones function to mobilize histones during repair.

Show MeSH

Related in: MedlinePlus

Histone dynamics at late steps of NER in mammals. Newly synthesized H3.1 histone variants in dimers with H4 (black) are deposited at UVC damage sites [40,41]. De novo histone deposition is coupled to repair synthesis via a direct interaction between the specific H3.1 histone chaperone CAF-1 (purple) and the polymerase sliding clamp PCNA (yellow) [67]. The chaperone ASF-1 may be a donor of new H3.1 for CAF-1 and/or contribute to old histone recycling. The involvement of other histone variants and other chaperones in the new histone deposition process is still to be determined. The contribution of old histone recycling is also an open issue. H2A is ubiquitylated (orange) in a CAF-1-dependent manner [52]. This modification, reported to destabilize nucleosome structure [54], might contribute in concert with nucleosome remodelers (blue) to re-position newly formed nucleosomes after repair.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC3472782&req=5

f5-ijms-13-11895: Histone dynamics at late steps of NER in mammals. Newly synthesized H3.1 histone variants in dimers with H4 (black) are deposited at UVC damage sites [40,41]. De novo histone deposition is coupled to repair synthesis via a direct interaction between the specific H3.1 histone chaperone CAF-1 (purple) and the polymerase sliding clamp PCNA (yellow) [67]. The chaperone ASF-1 may be a donor of new H3.1 for CAF-1 and/or contribute to old histone recycling. The involvement of other histone variants and other chaperones in the new histone deposition process is still to be determined. The contribution of old histone recycling is also an open issue. H2A is ubiquitylated (orange) in a CAF-1-dependent manner [52]. This modification, reported to destabilize nucleosome structure [54], might contribute in concert with nucleosome remodelers (blue) to re-position newly formed nucleosomes after repair.

Mentions: The analysis of nucleosome dynamics during NER was then taken one step further by examining the role of specific histone variants. Indeed, most histones exist as distinct variants which differ in their amino-acid sequences, their expression profiles, and their timing and/or sites of incorporation into chromatin [5]. So far, the efforts towards investigating histone variant dynamics coupled to NER have been focused on the replicative H3.1 variant that is synthesized mostly in S phase and incorporated into nucleosomes in a DNA synthesis-coupled manner. In vitro experiments demonstrated that epitope-tagged H3.1 histone is deposited onto immobilized UV-damaged templates [41] (Figure 3). These data were then further strengthened in vivo in human cells transiently expressing Flag-HA-tagged H3.1. Upon local UVC irradiation, newly synthetized H3.1 histones accumulate at damage sites in a manner coupled to repair synthesis [40]. This study puts forward new H3.1 histone incorporation as critical in chromatin restoration after repair of UVC lesions (Figure 5).


Chromatin dynamics during nucleotide excision repair: histones on the move.

Adam S, Polo SE - Int J Mol Sci (2012)

Histone dynamics at late steps of NER in mammals. Newly synthesized H3.1 histone variants in dimers with H4 (black) are deposited at UVC damage sites [40,41]. De novo histone deposition is coupled to repair synthesis via a direct interaction between the specific H3.1 histone chaperone CAF-1 (purple) and the polymerase sliding clamp PCNA (yellow) [67]. The chaperone ASF-1 may be a donor of new H3.1 for CAF-1 and/or contribute to old histone recycling. The involvement of other histone variants and other chaperones in the new histone deposition process is still to be determined. The contribution of old histone recycling is also an open issue. H2A is ubiquitylated (orange) in a CAF-1-dependent manner [52]. This modification, reported to destabilize nucleosome structure [54], might contribute in concert with nucleosome remodelers (blue) to re-position newly formed nucleosomes after repair.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472782&req=5

f5-ijms-13-11895: Histone dynamics at late steps of NER in mammals. Newly synthesized H3.1 histone variants in dimers with H4 (black) are deposited at UVC damage sites [40,41]. De novo histone deposition is coupled to repair synthesis via a direct interaction between the specific H3.1 histone chaperone CAF-1 (purple) and the polymerase sliding clamp PCNA (yellow) [67]. The chaperone ASF-1 may be a donor of new H3.1 for CAF-1 and/or contribute to old histone recycling. The involvement of other histone variants and other chaperones in the new histone deposition process is still to be determined. The contribution of old histone recycling is also an open issue. H2A is ubiquitylated (orange) in a CAF-1-dependent manner [52]. This modification, reported to destabilize nucleosome structure [54], might contribute in concert with nucleosome remodelers (blue) to re-position newly formed nucleosomes after repair.
Mentions: The analysis of nucleosome dynamics during NER was then taken one step further by examining the role of specific histone variants. Indeed, most histones exist as distinct variants which differ in their amino-acid sequences, their expression profiles, and their timing and/or sites of incorporation into chromatin [5]. So far, the efforts towards investigating histone variant dynamics coupled to NER have been focused on the replicative H3.1 variant that is synthesized mostly in S phase and incorporated into nucleosomes in a DNA synthesis-coupled manner. In vitro experiments demonstrated that epitope-tagged H3.1 histone is deposited onto immobilized UV-damaged templates [41] (Figure 3). These data were then further strengthened in vivo in human cells transiently expressing Flag-HA-tagged H3.1. Upon local UVC irradiation, newly synthetized H3.1 histones accumulate at damage sites in a manner coupled to repair synthesis [40]. This study puts forward new H3.1 histone incorporation as critical in chromatin restoration after repair of UVC lesions (Figure 5).

Bottom Line: Several decades of analysis combining in vitro and in vivo studies in various model organisms ranging from yeast to human have markedly increased our understanding of the mechanisms underlying chromatin disorganization upon damage detection and re-assembly after repair.We also highlight how these methods have provided key mechanistic insight into histone dynamics coupled to repair in mammals, raising new issues about the maintenance of chromatin integrity.In particular, we discuss how NER factors and central players in chromatin dynamics such as histone modifiers, nucleosome remodeling factors, and histone chaperones function to mobilize histones during repair.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Chromatin Dynamics, Curie Institute Research Centre, 75248 Paris Cedex 5, France; E-Mail: salome.adam@curie.fr ; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 218, 75248 Paris Cedex 5, France.

ABSTRACT
It has been a long-standing question how DNA damage repair proceeds in a nuclear environment where DNA is packaged into chromatin. Several decades of analysis combining in vitro and in vivo studies in various model organisms ranging from yeast to human have markedly increased our understanding of the mechanisms underlying chromatin disorganization upon damage detection and re-assembly after repair. Here, we review the methods that have been developed over the years to delineate chromatin alterations in response to DNA damage by focusing on the well-characterized Nucleotide Excision Repair (NER) pathway. We also highlight how these methods have provided key mechanistic insight into histone dynamics coupled to repair in mammals, raising new issues about the maintenance of chromatin integrity. In particular, we discuss how NER factors and central players in chromatin dynamics such as histone modifiers, nucleosome remodeling factors, and histone chaperones function to mobilize histones during repair.

Show MeSH
Related in: MedlinePlus