Repair of Chromatin

Indeed, packing DNA into minichromosomes results in less efficient repair than that observed in naked DNA, presumably because of reduced accessibility of the repair factors (Sugasawa et al, 1993 Wang et at, 1991). 

These studies used randomly damaged DNA and could not distinguish between inhibition of repair in the nucleosome core or linker DNA. More recent studies have used the in vitro assembly of nucleosomes containing site-specific DNA lesions within the core particle and either purified repair factors or mammalian cell extracts to examine in more detail the effect of chromatin structure on excision repair. It was determined that UV-induced photolesions as well as AAF- and cisplatin-modified bases located in nucleosome cores are repaired at a 5- to 10-fold reduced rate relative to the same lesions within the same sequence context in naked DNA (Hara and Sancar, 2002, 2003 Hara et al., 2000 Wang et aL, 2003). 

The mechanistic details of the dual-incision event are well characterized, especially in bacteria, so it was quite surprising when Goosen and colleagues reported the discovery of Gho, a previously unknown UvrC homolog that functions in E. coli excision repair (see Van Houten et al., 2002). Are there other repair protein homologs, particularly in the more complex human cell, and what role might they have in excision repair  

and Kingston, R. E. (2000). What does chromatiii remodeling mean  

Aravind, L., Walker, D. R., and Koonin, E. V. (1999). Conserved domains in DNA repair proteins and evolution of repair systems. Nucleic Acids Res. 27, 1223-1242. 

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Maezawa, H. Suzuki, M. Yokoya, A. Usami, N. Kobayashi, K. Repair of chromatin breaks produced by monochromatic X-rays with energies of around K-shell absorption edge of phosphorus in V79 Cells Photon Factory Activity Report 1997, Vol. 14, 420. 

The core unit of the chromatin, the nucleosome, consists of histones arranged as an octamer consisting of a (H3/ H4)2-tetramer complexed with two histone H2A/H2B dimers. Accessibility to DNA-binding proteins (for replication, repair, or transcription) is achieved by posttranslational modifications of the amino-termini of the histones, the histone tails phosphorylation, acetylation, methylation, ubiquitination, and sumoyla-tion. Especially acetylation of histone tails has been linked to transcriptional activation, leading to weakened interaction of the core complexes with DNA and subsequently to decondensation of chromatin. In contrast, deacetylation leads to transcriptional repression. As mentioned above, transcriptional coactivators either possess HAT activity or recruit HATs. HDACs in turn act as corepressors. 

How does PARP-Fs role as a nucleosome-binding protein and modulator of chromatin structure, which is evident under normal physiological conditions, impact PARP-1-dependent DNA repair, cell death, and inflammatory response pathways, which occur under pathophysiological conditions A number of different scenarios are possible. For example, PARP-l s chromatin-dependent activities may be critical for its function as a DNA repair protein, since the repair of genomic DNA must occur in the context of chromatin. In addition, nucleosome-stimulated autoPARylation may play a role in depleting cellular NAD+ pools in response to cellular stresses. Furthermore, PARP-Fs chromatin-dependent activities may help to regulate the expression of immune and inflammatory response genes. These possibilities will need to be examined in the future. 

Ultimately the DNA lesion is repaired by a short patch repair mechanism, which, in linker regions of nucleosomes or open regions of chromatin (where lesions are generally concentrated) is associated with minimal nucleosome rearrangement (Jones et al, 2001). 

SI39 (for mammals). The responsible kinases are members from phosphatidyli-nositol 3-kinase (PI3K)-like family kinases, which include ataxia telangiectasia mutated (ATM), AT-related (ATR), and DNA dependent protein kinase (DNA-PK) (Burma et al, 2001 Stiff et al, 2004 van Attikum and Gasser, 2005). Histone H2AX phosphorylation is directly related to repair of damaged chromatin (for details see chapter on Role of histone phosphorylation in chromatin dynamics and its implication in diseases ). 

These events include the inactivation by proteolysis, of PARP, so DNA repair does not take place, but significantly, ATP is not wasted. Detachment of chromatin from the nuclear... 

Accordingly, some effort has been devoted to studying the effects of cisplatin on transcription. In vitro experiments with RNA polymerases demonstrated that productive elongation activity was prematurely terminated by the whole spectrum of cisplatin-DNA adducts, but not by the /ran.y-DDP 1,3-intrastrand adducts [150-152], Selective bypass of trans-DDP adducts was also demonstrated in XPA cells, suggesting that repair of the DNA lesions did not contribute to differential transcription inhibition by the platinum compounds [153], In vivo, hormone-induced chromatin remodeling and subsequent transcription from the MMTV promoter was specifically inhibited by cisplatin [154], In this case, platinum adducts seemed to cause a decrease in the DNA binding of one of the transcription factors, NF1. Several chromatin-associated proteins, such as the linker histone protein HI or... 

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