Base excision repair in nucleosome substrates

Jagannathan, Indu; Cole, Hope A.; Hayes, Jeffrey J.

doi:10.1007/s10577-005-1020-7

Cited by 27 publications

(19 citation statements)

References 43 publications

(61 reference statements)

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“…APE1 has also been shown to enhance the efficiency of human UDG (hUDG, commonly known as hUNG2) (35), presumably by the same mechanism. Although it is not known whether APE1 stimulation of hUDG occurs in the context of NCPs, the presence (or absence) of APE1 in previous assessments of UDG activity on NCPs has been suggested to be a factor in discrepancies associated with the impact of uracil orientation (36). Whereas UDG activity appeared to be unaffected by uracil orientation when measuring uracil base excision (done in the absence of APE1) (21), measuring cleavage of the DNA as an indicator of UDG activity (with APE1) has shown orientation dependence in this study and elsewhere (22).…”

Section: Unbiased Udg/ape1 Activity At Uracils In Different Sequencementioning

confidence: 99%

Rotational dynamics of DNA on the nucleosome surface markedly impact accessibility to a DNA repair enzyme

Hinz

Rodriguez

Smerdon

2010

Proc. Natl. Acad. Sci. U.S.A.

102

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Histones play a crucial role in the organization of DNA in the nucleus, but their presence can prevent interactions with DNA binding proteins responsible for repair of DNA damage. Uracil is an abundant mutagenic lesion recognized by uracil DNA glycosylase (UDG) in the first step of base excision repair (BER). In nucleosome core particles (NCPs), we find substantial differences in UDGdirected cleavage at uracils rotationally positioned toward (U-In) or away from (U-Out) the histone core, or midway between these orientations (U-Mid). Whereas U-Out NCPs show a cleavage rate just below that of naked DNA, U-In and U-Mid NCPs have markedly slower rates of cleavage. Crosslinking of U-In DNA to histones in NCPs yields a greater reduction in cleavage rate but, surprisingly, yields a higher rate of cleavage in U-Out NCPs compared with uncrosslinked NCPs. Moreover, the next enzyme in BER, APE1, stimulates the activity of human UDG in U-Out NCPs, suggesting these enzymes interact on the surface of histones in orientations accessible to UDG. These data indicate that the activity of UDG likely requires "trapping" transiently exposed states arising from the rotational dynamics of DNA on histones.chromatin | DNA damage | glycosylase | histones | APE1 endonuclease

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Section: Unbiased Udg/ape1 Activity At Uracils In Different Sequencementioning

confidence: 99%

Rotational dynamics of DNA on the nucleosome surface markedly impact accessibility to a DNA repair enzyme

Hinz

Rodriguez

Smerdon

2010

Proc. Natl. Acad. Sci. U.S.A.

102

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“…Indeed, the BER pathway is the predominant mechanism for the repair of oxidative DNA damage; the oxidized base 8-oxoguanine can pair with both adenine and cytosine with, resulting in G:C to T:A transversions [5]. In addition, BER is also involved in the removal of uracil in DNA, which is formed by a spontaneous cytosine deamination process, resulting in erroneous U:G matching [6]. The colon epithelium is one of the most constantly regenerated tissues in the human body and, thus, is more vulnerable to a variety of mutagenic compounds present in the intestine and/or blood.…”

Section: Introductionmentioning

confidence: 99%

Effect of APE1 T2197G (Asp148Glu) Polymorphism on APE1, XRCC1, PARP1 and OGG1 Expression in Patients with Colorectal Cancer

Santos

Funck

Silva-Fernandes

et al. 2014

IJMS

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It has been hypothesized that genetic variation in base excision repair (BER) might modify colorectal adenoma risk. Thus, we evaluated the influence of APE1 T2197G (Asp148Glu) polymorphism on APE1, XRCC1, PARP1 and OGG1 expression in normal and tumor samples from patients with colorectal cancer. The results indicate a downregulation of OGG1 and an upregulation of XRCC1 expression in tumor tissue. Regarding the anatomical location of APE1, OGG1 and PARP-1, a decrease in gene expression was observed among patients with cancer in the rectum. In patients with or without some degree of tumor invasion, a significant downregulation in OGG1 was observed in tumor tissue. Interestingly, when taking into account the tumor stage, patients with more advanced grades (III and IV) showed a significant repression for APE1, OGG1 and PARP-1. XRCC1 expression levels were significantly enhanced in tumor samples and were correlated with all clinical and histopathological data. Concerning the polymorphism T2197G, GG genotype carriers exhibited a significantly reduced expression of genes of the BER repair system (APE1, XRCC1 and PARP1). In summary, our data show that patients with colorectal cancer present expression changes in several BER genes, suggesting a role for APE1, XRCC1, PARP1 and OGG1 and APE1 polymorphism in colorectal carcinogenesis.

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“…How BER acts on DNA organized into nucleosome, however, remains unclear, and the reported data exhibit some disagreements (5,6,25,33). For example, in one study (33), uracil DNA glycosylase (UDG) showed 3-to 10-fold-reduced accessibility in nucleosomes independently on rotational setting, while in other studies (5, 6), a 10-to 30-fold inhibition of UDG by the nucleosome and a strong dependence of UDG processing on the rotation position of the uracil was reported.…”

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confidence: 99%

ATP-Dependent Chromatin Remodeling Is Required for Base Excision Repair in Conventional but Not in Variant H2A.Bbd Nucleosomes

Menoni

Gasparutto

Hamiche

et al. 2007

Molecular and Cellular Biology

103

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In eukaryotes, base excision repair (BER) is responsible for the repair of oxidatively generated lesions. The mechanism of BER on naked DNA substrates has been studied in detail, but how it operates on chromatin remains unclear. Here we have studied the mechanism of BER by introducing a single 8-oxo-7,8-dihydroguanine (8-oxoG) lesion in the DNA of reconstituted positioned conventional and histone variant H2A.Bbd nucleosomes. We found that 8-oxoguanine DNA glycosylase, apurinic/apyrimidinic endonuclease, and polymerase ␤ activities were strongly reduced in both types of nucleosomes. In conventional nucleosomes SWI/SNF stimulated the processing of 8-oxoG by each one of the three BER repair factors to efficiencies similar to those for naked DNA. Interestingly, SWI/SNF-induced remodeling, but not mobilization of conventional nucleosomes, was required to achieve this effect. A very weak effect of SWI/SNF on the 8-oxoG BER removal in H2A.Bbd histone variant nucleosomes was observed. The possible implications of our data for the understanding of in vivo mechanisms of BER are discussed.Eukaryotic cells are constantly subjected to oxidative stress. The reactive oxygen species generated during cell metabolism react with the nucleobases and damage DNA at any moment of the cell life. 8-Oxo-7,8-dihydroguanine (8-oxoG), the major reactive oxygen species-induced oxidative lesion, is repaired by the base excision repair (BER) pathway (27). The first step in the BER pathway is the recognition and the removal of 8-oxoG by 8-oxoguanine DNA glycosylase (OGG1), a bifunctional Nglycosylase which exhibits both a glycosylase and an apurinic/ apyrimidinic (AP) lyase activity (38, 44). The DNA nicked by OGG1 at the site of the lesion (3Ј to the lesion) is then processed by an apurinic/apyrimidinic endonuclease (APE1), which creates a free 3Ј-hydroxyl group required for the gap filling by polymerase ␤ (Pol ␤). Finally, the 8-oxoG repair is completed by ligation of the nick by DNA ligase III (for a review, see reference 28).DNA in the eukaryotic cell is packaged into chromatin. The first level of chromatin organization, the nucleosome, consists of an octamer of core histones (two each of H2A, H2B, H3, and H4) around which ϳ150 bp of DNA is wrapped into two superhelical turns (45). In addition to the conventional histones, eukaryotic cells express histone variants, which are incorporated into chromatin and form variant nucleosomes (45). Histone variants are nonallelic isoforms of conventional histones and show various degrees of homology to their conventional counterparts (39). The recently identified histone variant H2A.Bbd (Barr body deficient), which exhibited only 48% identity with H2A, is found to be localized in transcriptionally active regions of the nucleus (8). H2A.Bbd nucleosomes have a more relaxed structure, they are less stable and more easily transcribed than conventional nucleosomes (14), and they are resistant to remodeling by SWI/SNF (3).The repair proteins catalyzing the different steps in BER on naked DNA substrates have ...

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Base excision repair in nucleosome substrates

Cited by 27 publications

References 43 publications

Rotational dynamics of DNA on the nucleosome surface markedly impact accessibility to a DNA repair enzyme

Rotational dynamics of DNA on the nucleosome surface markedly impact accessibility to a DNA repair enzyme

Effect of APE1 T2197G (Asp148Glu) Polymorphism on APE1, XRCC1, PARP1 and OGG1 Expression in Patients with Colorectal Cancer

ATP-Dependent Chromatin Remodeling Is Required for Base Excision Repair in Conventional but Not in Variant H2A.Bbd Nucleosomes

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