Neocarzinostatin-induced DNA base release accompanied by staggered oxidative cleavage of the complementary strand.

Povirk, Lawrence F.; Houlgrave, C. W.; Han, Yi-Hong

doi:10.1016/s0021-9258(19)77626-1

Cited by 49 publications

(27 citation statements)

References 16 publications

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“…This MDS represents only a small proportion of bleomycin-induced DNA damage but accounts for the majority of neocarzinostatin-induced damage (44). The structure of the bleomycin MDS is unknown, however, neocarzinostatin produces an AP site 2 nt 5′ of a strand break (45). High concentrations of endo III were also required to cleave these complex lesions in vitro (45).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to removing the modified pyrimidine by cutting the N-glycosyl *To whom correspondence should be addressed. Tel: +1 802 656 2164; Fax: +1 802 656 8749; Email: swallace@zoo.uvm.edu Present addresses: + Department of Molecular and Cellular Physiology, Louisiana State Medical Center, Shreveport, LA 71130, USA and § Pentose Pharmaceuticals Inc., 45 Moulton Street, Cambridge, MA 02138, USA bond, the associated lyase activity of these enzymes cleaves the DNA backbone, either by β elimination in the case of endo III (10) or by β,δ elimination in the case of endo VIII (11). Furthermore, both enzymes cleave at sites of base loss with a 10-fold greater efficiency than at a damaged pyrimidine site (Hatahet and Wallace, unpublished observations).…”

Section: Introductionmentioning

confidence: 99%

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Multiply damaged sites in DNA: interactions with Escherichia coli endonucleases III and VIII

Harrison

1998

Nucleic Acids Research

114

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Bursts of free radicals produced by ionization of water in close vicinity to DNA can produce clusters of opposed DNA lesions and these are termed multiply damaged sites (MDS). How MDS are processed by the Escherichia coli DNA glycosylases, endonuclease (endo) III and endo VIII, which recognize oxidized pyrimidines, is the subject of this study. Oligonucleotide substrates were constructed containing a site of pyrimidine damage or an abasic (AP) site in close proximity to a single nucleotide gap, which simulates a free radical-induced single-strand break. The gap was placed in the opposite strand 1, 3 or 6 nt 5' or 3' of the AP site or base lesion. Endos III and VIII were able to cleave an AP site in the MDS, no matter what the position of the opposed strand break, although cleavage at position one 5' or 3' was reduced compared with cleavage at positions three or six 5' or 3'. Neither endo III nor endo VIII was able to remove the base lesion when the gap was positioned 1 nt 5' or 3' in the opposite strand. Cleavage of the modified pyrimidine by endo III increased as the distance increased between the base lesion and the opposed strand break. With endo VIII, however, DNA breakage at the site of the base lesion was equivalent to or less when the gap was positioned 6 nt 3' of the lesion than when the gap was 3 nt 3' of the lesion. Gel mobility shift analysis of the binding of endo VIII to an oligonucleotide containing a reduced AP (rAP) site in close opposition to a single nucleotide gap correlated with cleavage of MDS substrates by endo VIII. If the strand break in the MDS was replaced by an oxidized purine, 7,8-dihydro-8-oxoguanine (8-oxoG), neither endo VIII cleavage nor binding were perturbed. These data show that processing of oxidized pyrimidines by endos III and VIII was strongly influenced by the position and type of lesion in the opposite strand, which could have a significant effect on the biological outcome of the MDS lesion.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multiply damaged sites in DNA: interactions with Escherichia coli endonucleases III and VIII

Harrison

1998

Nucleic Acids Research

114

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“…Exposure of MEFs to neocarzinostatin (NCS), which also causes DSBs like IR (Povirk et al, 1988), did not change the protein level of 53BP1 (unpublished data). Similar to IR, 53BP1 focal accumulation was diminished in NCS-treated H2AX KO MEFs when compared with WT MEFs (Fig.…”

Section: ␥ -H2ax Is Dispensable For the Focal Accumulation Of Blm And 53bp1 During Replicational Stressmentioning

confidence: 94%

Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest

Sengupta

Robles

Linke

et al. 2004

The Journal of Cell Biology

123

113

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Bloom's syndrome is a rare autosomal recessive genetic disorder characterized by chromosomal aberrations, genetic instability, and cancer predisposition, all of which may be the result of abnormal signal transduction during DNA damage recognition. Here, we show that BLM is an intermediate responder to stalled DNA replication forks. BLM colocalized and physically interacted with the DNA damage response proteins 53BP1 and H2AX. Although BLM facilitated physical interaction between p53 and 53BP1, 53BP1 was required for efficient accumulation of both BLM and p53 at the sites of stalled replication. The accumulation of BLM/53BP1 foci and the physical interaction between them was independent of γ-H2AX. The active Chk1 kinase was essential for both the accurate focal colocalization of 53BP1 with BLM and the consequent stabilization of BLM. Once the ATR/Chk1- and 53BP1-mediated signal from replicational stress is received, BLM functions in multiple downstream repair processes, thereby fulfilling its role as a caretaker tumor suppressor.

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“…Recently it has been found that such lesions may be generated by the abstraction of a hydrogen atom from the Cl' of the Cyt residue in AGC to form 2-deoxyribonolactone with intact phosphodiester linkages [20,21]. In contrast to other strand breaks, the abasic site at Cyt is always accompanied by a direct break on the complementary strand two nucleotides to the 3'-side at Thy [22]. It is believed that the activation of NCS by thiol (or sodium borohydride) occurs via nucleophilic addition at C12 and rearrangement of the bicyclic ene-diyne core into a diradical species with radical centers at the C2 and C6 atoms [3,12] (Fig.…”

Section: Introductionmentioning

confidence: 99%

Molecular models of neocarzinostatin damage of DNA: analysis of sequence dependence in 5′GAGCG:5′CGCTC

Gałat

Goldberg

1990

Nucl Acids Res

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Model building and molecular mechanics and dynamics calculations have been performed on a number of complexes of the post-activated form of the neocarzinostatin chromophore (NCS) with the B-DNA oligomer 5'GAGCG:5'CGCTC. Stable structures with the naphthoic acid moiety intercalated at all base pairs can be constructed. The observed bistranded lesions consisting of an abasic site at the Cyt residue in AGC and a direct break at the Thy residue on the complementary strand can be explained by assuming that NCS in the (R,R) form intercalates between the Ade2-Thy9/Gua3-Cyt8 base step with its 'diradical' core oriented towards the 3'-end of the (+) strand. Sites at C5', C4' and C1' in the minor groove are within a short enough distance from the two radical centers on NCS to permit hydrogen atom abstraction and the formation of the bistranded lesions. Strand cleavage at Thy9 may occur as a single lesion if NCS is intercalated into the Gua3-Cyt8/Cyt4-Gua7 base step with its active core towards the 3'-end of the (-) strand. The results are analyzed, and the utility and limitations of this type of model building are discussed.

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Neocarzinostatin-induced DNA base release accompanied by staggered oxidative cleavage of the complementary strand.

Cited by 49 publications

References 16 publications

Multiply damaged sites in DNA: interactions with Escherichia coli endonucleases III and VIII

Multiply damaged sites in DNA: interactions with Escherichia coli endonucleases III and VIII

Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest

Molecular models of neocarzinostatin damage of DNA: analysis of sequence dependence in 5′GAGCG:5′CGCTC

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