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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.

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Histone dynamics at early steps of NER in mammals. The GGR (Global Genome Repair) factor DDB2 is recruited to the lesion (red triangle), where it promotes chromatin decompaction and histone displacement [32]. In conjunction with DDB1, Cul4 and RBX1, DDB2 forms an E3-ubiquitin ligase complex, which triggers ubiquitylation (orange) of several substrates. In particular, various core histones (H2A, H3 and H4) are ubiquitylated [48–53], which is thought to destabilize nucleosome structure and to promote histone loss from damaged chromatin [49,54]. The fate of histones displaced from damaged chromatin regions (degradation or recycling by histone chaperones) is still under investigation. In addition to a possible eviction of histones from damaged nucleosomes, histone dynamics during NER likely involves histone mobilization/sliding by nucleosome remodeling factors such as INO80, likely recruited via its interaction with DDB1 [55] and SWI/SNF, recruited concomitantly with the GGR factor XPC [56–59]. In addition to their association with repair factors, binding to DNA damage-induced histone modifications could be another mechanism for recruiting chromatin remodelers. During TCR (Transcription Coupled Repair), stalled RNAPII (green) is recognized by CSB, a SWI/SNF-like ATPase whose function in chromatin remodeling in vivo is still unclear [60].
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f4-ijms-13-11895: Histone dynamics at early steps of NER in mammals. The GGR (Global Genome Repair) factor DDB2 is recruited to the lesion (red triangle), where it promotes chromatin decompaction and histone displacement [32]. In conjunction with DDB1, Cul4 and RBX1, DDB2 forms an E3-ubiquitin ligase complex, which triggers ubiquitylation (orange) of several substrates. In particular, various core histones (H2A, H3 and H4) are ubiquitylated [48–53], which is thought to destabilize nucleosome structure and to promote histone loss from damaged chromatin [49,54]. The fate of histones displaced from damaged chromatin regions (degradation or recycling by histone chaperones) is still under investigation. In addition to a possible eviction of histones from damaged nucleosomes, histone dynamics during NER likely involves histone mobilization/sliding by nucleosome remodeling factors such as INO80, likely recruited via its interaction with DDB1 [55] and SWI/SNF, recruited concomitantly with the GGR factor XPC [56–59]. In addition to their association with repair factors, binding to DNA damage-induced histone modifications could be another mechanism for recruiting chromatin remodelers. During TCR (Transcription Coupled Repair), stalled RNAPII (green) is recognized by CSB, a SWI/SNF-like ATPase whose function in chromatin remodeling in vivo is still unclear [60].

Mentions: Besides its likely role in giving access to repair machineries, histone eviction may also be a way to eliminate damaged histones (Figure 4). Indeed, UV irradiation can lead to the production of reactive oxygen species and free radicals via photosensitization mechanisms [33]. Histone proteins oxidized by such reactive molecules may then be targeted for degradation [34]. An alternative possibility is that histones removed from damaged chromatin regions are recycled by histone chaperones (Figure 4) and contribute to chromatin reorganization after DNA repair. Further studies on the fate of displaced histones will be required to understand how the original information conveyed by chromatin via histone variants and modifications can be preserved.


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

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

Histone dynamics at early steps of NER in mammals. The GGR (Global Genome Repair) factor DDB2 is recruited to the lesion (red triangle), where it promotes chromatin decompaction and histone displacement [32]. In conjunction with DDB1, Cul4 and RBX1, DDB2 forms an E3-ubiquitin ligase complex, which triggers ubiquitylation (orange) of several substrates. In particular, various core histones (H2A, H3 and H4) are ubiquitylated [48–53], which is thought to destabilize nucleosome structure and to promote histone loss from damaged chromatin [49,54]. The fate of histones displaced from damaged chromatin regions (degradation or recycling by histone chaperones) is still under investigation. In addition to a possible eviction of histones from damaged nucleosomes, histone dynamics during NER likely involves histone mobilization/sliding by nucleosome remodeling factors such as INO80, likely recruited via its interaction with DDB1 [55] and SWI/SNF, recruited concomitantly with the GGR factor XPC [56–59]. In addition to their association with repair factors, binding to DNA damage-induced histone modifications could be another mechanism for recruiting chromatin remodelers. During TCR (Transcription Coupled Repair), stalled RNAPII (green) is recognized by CSB, a SWI/SNF-like ATPase whose function in chromatin remodeling in vivo is still unclear [60].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4-ijms-13-11895: Histone dynamics at early steps of NER in mammals. The GGR (Global Genome Repair) factor DDB2 is recruited to the lesion (red triangle), where it promotes chromatin decompaction and histone displacement [32]. In conjunction with DDB1, Cul4 and RBX1, DDB2 forms an E3-ubiquitin ligase complex, which triggers ubiquitylation (orange) of several substrates. In particular, various core histones (H2A, H3 and H4) are ubiquitylated [48–53], which is thought to destabilize nucleosome structure and to promote histone loss from damaged chromatin [49,54]. The fate of histones displaced from damaged chromatin regions (degradation or recycling by histone chaperones) is still under investigation. In addition to a possible eviction of histones from damaged nucleosomes, histone dynamics during NER likely involves histone mobilization/sliding by nucleosome remodeling factors such as INO80, likely recruited via its interaction with DDB1 [55] and SWI/SNF, recruited concomitantly with the GGR factor XPC [56–59]. In addition to their association with repair factors, binding to DNA damage-induced histone modifications could be another mechanism for recruiting chromatin remodelers. During TCR (Transcription Coupled Repair), stalled RNAPII (green) is recognized by CSB, a SWI/SNF-like ATPase whose function in chromatin remodeling in vivo is still unclear [60].
Mentions: Besides its likely role in giving access to repair machineries, histone eviction may also be a way to eliminate damaged histones (Figure 4). Indeed, UV irradiation can lead to the production of reactive oxygen species and free radicals via photosensitization mechanisms [33]. Histone proteins oxidized by such reactive molecules may then be targeted for degradation [34]. An alternative possibility is that histones removed from damaged chromatin regions are recycled by histone chaperones (Figure 4) and contribute to chromatin reorganization after DNA repair. Further studies on the fate of displaced histones will be required to understand how the original information conveyed by chromatin via histone variants and modifications can be preserved.

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