Abstract:To investigate the role of chromatin remodeling in nucleotide excision repair, we prepared mononucleosomes with a 200-bp duplex containing an acetylaminofluorene-guanine (AAF-G) adduct at a single site. DNase I footprinting revealed a well-phased nucleosome structure with the AAF-G adduct near the center of twofold symmetry of the nucleosome core. This mononucleosome substrate was used to examine the effect of the SWI/SNF remodeling complex on the activity of human excision nuclease reconstituted from six puri… Show more
“…In vitro, the ATP-dependent chromatin remodeler ACF can facilitate the dual incision step of NER within the linker DNA of a dinucleosomal template, although not within the nucleosome core particle [9]. Similarly, the ATP dependent chromatin remodeler SWI/ SNF can facilitate repair within the nucleosome core particle by a reconstituted human NER system [57]. It is possible that the addition of histone chaperones may further increase the efficiency of NER in vitro by their ability to unpackage chromatin, but this has not yet been experimentally demonstrated.…”
Section: Chromatin Assembly During Excision Repairmentioning
Current research is demonstrating that the packaging of the eukaryotic genome together with histone proteins into chromatin is playing a fundamental role in DNA repair and the maintenance of genomic integrity. As is well established to be the case for transcription, the chromatin structure dynamically changes during DNA repair. Recent studies indicate that the complete removal of histones from DNA and their subsequent reassembly onto DNA accompanies DNA repair. This review will present evidence indicating that chromatin disassembly and reassembly occur during DNA repair and that these are critical processes for cell survival after DNA repair. Concomitantly, candidate proteins utilized for these processes will be highlighted.
“…In vitro, the ATP-dependent chromatin remodeler ACF can facilitate the dual incision step of NER within the linker DNA of a dinucleosomal template, although not within the nucleosome core particle [9]. Similarly, the ATP dependent chromatin remodeler SWI/ SNF can facilitate repair within the nucleosome core particle by a reconstituted human NER system [57]. It is possible that the addition of histone chaperones may further increase the efficiency of NER in vitro by their ability to unpackage chromatin, but this has not yet been experimentally demonstrated.…”
Section: Chromatin Assembly During Excision Repairmentioning
Current research is demonstrating that the packaging of the eukaryotic genome together with histone proteins into chromatin is playing a fundamental role in DNA repair and the maintenance of genomic integrity. As is well established to be the case for transcription, the chromatin structure dynamically changes during DNA repair. Recent studies indicate that the complete removal of histones from DNA and their subsequent reassembly onto DNA accompanies DNA repair. This review will present evidence indicating that chromatin disassembly and reassembly occur during DNA repair and that these are critical processes for cell survival after DNA repair. Concomitantly, candidate proteins utilized for these processes will be highlighted.
“…BAF47-deficient cells are hypersensitive to genotoxic stress (Klochendler-Yeivin et al, 2006), and re-expression of BRG1 in BRG1-deficient SW13 cells renders the cells resistant to ultravioletinduced DNA damage (Gong et al, 2008). SWI/SNF facilitates the repair of cyclobutane pyrimidine dimers (Gaillard et al, 2003) and acetylaminofluorene-guanine adducts (Hara and Sancar, 2002) in a nucleosomal context. Studies carried out in vivo indicate that SWI/ SNF is recruited to double-strand break sites (Chai et al, 2005), and the inactivation of the SWI/SNF complex results in inefficient DNA double-strand break repair in vivo (Park et al, 2006).…”
The mammalian SWI/SNF complexes mediate ATPdependent chromatin remodeling processes that are critical for differentiation and proliferation. Not surprisingly, loss of SWI/SNF function has been associated with malignant transformation, and a substantial body of evidence indicates that several components of the SWI/SNF complexes function as tumor suppressors. This review summarizes the evidence that underlies this conclusion, with particular emphasis upon the two catalytic subunits of the SWI/SNF complexes, BRM, the mammalian ortholog of SWI2/SNF2 in yeast and brahma in Drosophila, and Brahma-related gene-1 (BRG1).
“…Biochemical studies showed that nucleosome assembly on in vitro NER substrate was severely inhibitory to the dual incision in either cell-extractbased or reconstituted assays (16)(17)(18). This inhibition can be mitigated by the presence of the yeast SWI/SNF complex in the reaction (19,20), which suggests that chromatin reconfiguration is likely a necessary step preceding NER. However, which ATPdependent remodeling complex or complexes provide the principal in vivo remodeling activity in aiding NER is unknown.…”
The creation of accessible DNA in the context of chromatin is a key step in many DNA functions. To reveal how ATP-dependent chromatin remodeling activities impact DNA repair, we constructed mammalian genetic models for the INO80 chromatin remodeling complex and investigated the impact of loss of INO80 function on the repair of UV-induced photo lesions. We showed that deletion of two core components of the INO80 complex, INO80 and ARP5, significantly hampered cellular removal of UV-induced photo lesions but had no significant impact on the transcription of nucleotide excision repair (NER) factors. Loss of INO80 abolished the assembly of NER factors, suggesting that prior chromatin relaxation is important for the NER incision process. Ino80 and Arp5 are enriched to UV-damaged DNA in an NER-incision-independent fashion, suggesting that recruitment of the remodeling activity likely takes place during the initial stage of damage recognition. These results demonstrate a critical role of INO80 in creating DNA accessibility for the NER pathway and provide direct evidence that repair of UV lesions and perhaps most bulky adduct lesions requires chromatin reconfiguration.DNA damage | DNA repair | chromatin | remodeling T he highly condensed nature of the chromatin assembly restricts the interaction of DNA with most nuclear factors. To create accessible DNA for various nuclear events, chromatin dynamics is regulated by the coordinated actions of two types of cellular mechanisms, posttranslational modifications of the core histones and ATP-dependent chromatin remodeling. Whereas covalent histone modifications, instigated mainly from regulation of yeast gene transcription, have been extensively studied, less is known about the chromatin remodeling process and how chromatin remodeling impacts various nuclear events.ATP-dependent chromatin remodeling is catalyzed by a distinct class of enzymes that comprises four families of structurally related ATP-dependent protein complexes (1). Biological activities of these complexes, defined by a variety of in vitro assays, include disruption of histone-DNA contact within nucleosomes, increased accessibility of nucleosomal DNA to transcription factors or restriction endonucleases, and cis and trans movement of histone octamers (2, 3). The INO80 chromatin remodeling complex was identified from the ino80-1 mutant defective in inositol/choline response (4-6). It contains the Ino80 ATPase, which belongs to the SNF/SWI2 superfamily (7). The Ino80 ATPase associates with 14 proteins to form a 1-MDa complex exhibiting 3′-5′ helicase activity (6,8). The INO80 complex also contains three actinrelated proteins (ARPs), of which ARP5 and ARP8 are specific to the INO80 complex. Deletion of either INO80-specific ARP compromises the ATPase activity of the remaining complex and gives rise to DNA-damage-sensitive phenotypes indistinguishable to the INO80 null mutant (9). Purification of human INO80 revealed a complex with virtually identical core components and a role in transcription (10, 11), indicating ...
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