Relationship between DNA Methylation and Mutational Patterns Induced by a Sequence Selective Minor Groove Methylating Agent

Kelly, Jack; Inga, Alberto; Chen, Fa Xian; Dande, Prasad; Shah, Deesha; Monti, Paola; Aprile, Anna; Burns, Philip A.; Scott, Gina B.; Abbondandolo, Angelo; Gold, Barry; Fronza, Gilberto

doi:10.1074/jbc.274.26.18327

Cited by 37 publications

(74 citation statements)

References 33 publications

(50 reference statements)

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“…A panel of 61 p53 mutants obtained in previous studies (Inga et al, 1997b(Inga et al, , 1998Kelly et al, 1999;Monti et al, 2000;Campomenosi et al, 2001;Tada et al, 2001) was used to validate the p73 interference assay (Tables 2 and 3). This panel included four mutants (Ser99Phe, Ser99Tyr, Ser314Phe, Arg337Ser) whose amino acid substitutions were located outside the crystallized portion of the p53 core protein (Cho et al, 1994), one truncated protein (Leu201stop) and 56 mutants localized in different domains of the protein.…”

Section: Comparison Of P53 and P73b Transactivation Capability In Yeastmentioning

confidence: 99%

“…The expression of wildtype p53 conferred adenine prototrophy (white, normal size colonies), while the expression of a mutant p53 unable to transactivate the ADE2 gene conferred adenine auxotrophy (small red colonies). The 61 mutant (pLS76) plasmids tested were obtained in different studies using the yeast functional assay as mutagenesis tool (Inga et al, 1997b(Inga et al, , 1998Kelly et al, 1999;Monti et al, 2000;Campomenosi et al, 2001) or through the characterization of the p53 status in human tumors and a generous gift of Dr Tim Crook). …”

Section: Strains Vectors and Mediamentioning

confidence: 99%

“…We first examined the ability of p73b to transactivate the ADE2 gene in different strains. Then we determined the ability of a panel of 61 p53 mutants (Inga et al, 1997b(Inga et al, , 1998Kelly et al, 1999;Monti et al, 2000;Tada et al, 2001) to inhibit p73b transcription in yIG397. Finally, the influence of a common R/P polymorphism at codon 72 on the ability of p53 mutants to interact with p73b was also studied.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the p53 mutants ability to inhibit p73β transactivation using a yeast-based functional assay

Monti¹,

Campomenosi

Ciribilli³

et al. 2003

Oncogene

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p53 is the most frequently altered tumor suppressor gene in a wide spectrum of human tumors. The large majority of p53 mutations observed in tumors are missense mutations. The p73 gene, encoding a protein with significant sequence similarity to p53, expresses multiple transcription-competent spliced variants, or transcriptionincompetent forms (i.e. DNp73). It was clearly shown that p73 transactivation from a p53-responsive promoter is inhibited by some tumor-derived p53 mutants in eucaryotic cells. In this study, we adapted a yeast-based p53 functional assay for the analysis of the influences of different p53 mutants on the activity of one of the p73 isoforms, namely p73b. We determined the ability of a panel of 61 p53 mutants to inhibit p73b activity following the net transcription of the ADE2 color (red/white) reporter gene driven by a p53-responsive promoter. By analysing a large number of mutants, we could conclude that interference: (a) is a quite frequent phenomenon (more than 70% of p53 mutants analysed are interfering); (b) is not confined to p53 mutations located in particular topological regions of the DNA binding domain; (c) does not appear to be dependent on the kind of side chains introduced at a specific position; (d) appears to significantly correlate with evolutionary conservation of the mutated p53 codon, frequency of occurrence of the mutation in tumors. The influence of a common R/P polymorphism at codon 72 on the ability of p53 mutants to interfere with p73b was also studied. Two sets of polymorphic variants (R and P) for 14 mutants were constructed and analysed. In all cases, the R/P 72 polymorphism was phenotypically irrelevant. In conclusion, our results suggest that the interpretation of the biological effects of p53 mutants should take into consideration the possibility that p53 mutants show loss or gain of function also through the interference with p53 family members.

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Section: Comparison Of P53 and P73b Transactivation Capability In Yeastmentioning

confidence: 99%

Section: Strains Vectors and Mediamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Characterization of the p53 mutants ability to inhibit p73β transactivation using a yeast-based functional assay

Monti¹,

Campomenosi

Ciribilli³

et al. 2003

Oncogene

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“…9 This is specially the case of methylating agents that generate almost exclusively N3-MeA (499%), such as MeOSO 2 (CH 2 ) 2 -lexitropsin (Me-Lex), a methyl sulfonate ester tethered to N-methylpyrrolecarboxamide dipeptide that targets A/T rich sequences located in the DNA minor groove. 10,11 Conversely, in the case of the imidazotetrazine temozolomide, which alkylates DNA at different base sites (70% N7-G, 9% N3-A, 5% O 6 -G), the low levels of N3-MeA adducts generated by the drug are rapidly repaired by BER system and do not substantially contribute to the overall toxicity of the agent. 12 The N7-methylguanine adduct appears to have little or no lethal effects, whereas O 6 -methylguanine (O 6 -MeG) is generally considered the main cytotoxic and mutagenic lesion produced by temozolomide.…”

Section: Introductionmentioning

confidence: 99%

Poly (ADP-ribose) polymerase inhibitor increases apoptosis and reduces necrosis induced by a DNA minor groove binding methyl sulfonate ester

et al. 2001

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The poly(ADP-ribose) polymerase (PARP) is involved in cell recovery from DNA damage, such as methylation of N3-adenine, that activates the base excision repair process. In the present study we demonstrated that MeOSO 2 (CH 2 ) 2 -lexitropsin (Me-Lex), a methylating agent that almost exclusively produces N3-methyladenine, induced different modalities of cell death in human leukemic cell lines, depending on the presence of PARP inhibitor. Growth inhibition, provoked by the combination of Me-Lex and PARP inhibitor, was associated with a marked down-regulation of c-myc, increased generation of single strand breaks and apoptosis. When used as single agent, at concentrations that saturated cell repair ability, Me-Lex induced mainly cell death by necrosis. Surprisingly, addition of a PARP inhibitor enhanced apoptosis and reduced the early appearance of necrosis. Telomerase activity was completely suppressed in cells exposed to Me-Lex alone, by 24 h after treatment, whereas it did not change when Me-Lex was combined with PARP inhibitor. Thereafter, inhibition of telomerase was observed with both treatments. The results suggest new insights on different modalities of cell death induced by high levels of N3-methyladenine per se, or by the methylated base in the presence of PARP inhibitor. Cell Death and Differentiation (2001) 8, 817 ± 828.

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“…Of particular interest are non-coding potentially toxic lesions, such as 3MeA (10,11,39). Even though 3MeA lesions spontaneously depurinate with a half-life of only 24 h at neutral pH, nearly every species has evolved an efficient 3MeA DNA glycosylase that rapidly removes this adduct from the genome, suggesting that this lesion is of sufficient biological impact to justify a system of very rapid removal.…”

Section: Discussionmentioning

confidence: 99%

In vivo repair of methylation damage in Aag 3-methyladenine DNA glycosylase null mouse cells

Smith

2000

Nucleic Acids Research

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3-Methyladenine (3MeA) DNA glycosylases initiate base excision repair by removing 3MeA. These glycosylases also remove a broad spectrum of spontaneous and environmentally induced base lesions in vitro. Mouse cells lacking the Aag 3MeA DNA glycosylase (also known as the Mpg, APNG or ANPG DNA glycosylase) are susceptible to 3MeA-induced S phase arrest, chromosome aberrations and apoptosis, but it is not known if Aag is solely responsible for repair of 3MeA in vivo. Here we show that in Aag -/-cells, 3MeA lesions disappear from the genome slightly faster than would be expected by spontaneous depurination alone, suggesting that there may be residual repair of 3MeA. However, repair of 3MeA is at least 10 times slower in Aag -/-cells than in Aag +/+ cells. Consequently, 24 h after exposure to [ 3 H]MNU, 30% of the original 3MeA burden is intact in Aag -/-cells, while 3MeA is undetectable in Aag +/+ cells. Thus, Aag is the major DNA glycosylase for 3MeA repair. We also investigated the in vivo repair kinetics of another Aag substrate, 7-methylguanine. Surprisingly, 7-methylguanine is removed equally efficiently in Aag +/+ and Aag -/-cells, suggesting that another DNA glycosylase acts on lesions previously thought to be repaired by Aag.

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Relationship between DNA Methylation and Mutational Patterns Induced by a Sequence Selective Minor Groove Methylating Agent

Cited by 37 publications

References 33 publications

Characterization of the p53 mutants ability to inhibit p73β transactivation using a yeast-based functional assay

Characterization of the p53 mutants ability to inhibit p73β transactivation using a yeast-based functional assay

Poly (ADP-ribose) polymerase inhibitor increases apoptosis and reduces necrosis induced by a DNA minor groove binding methyl sulfonate ester

In vivo repair of methylation damage in Aag 3-methyladenine DNA glycosylase null mouse cells

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