DNA repair domains within a human gene: selective repair of sequences near the transcription initiation site.

Tu, Yuqing; Tornaletti, Silvia; Pfeifer, Gerd P.

doi:10.1002/j.1460-2075.1996.tb00400.x

Cited by 111 publications

(106 citation statements)

References 52 publications

(70 reference statements)

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“…For example, Tu et al (1996) ®nd that only about half of the U.V.-induced cyclobutane pyrimidine dimers formed in the promoter region of human jun are repaired after 24 h. Although there are important di erences in global repair in human and rodent cells, persistent DNA damage in mouse (12)1/CA cells might generate a persistent signal, which cannot be transmitted as long as the block imposed by salicylate is in place. The correlation between the longevity of the damage and the signal eliminates the possibility that short-lived stimuli, such as changes in cellular redox pathways following U.V.-irradiation, trigger the activation of p53.…”

Section: Discussionmentioning

confidence: 99%

The p53 activation and apoptosis induced by DNA damage are reversibly inhibited by salicylate

Chernov

Stark

1997

Oncogene

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Section: Discussionmentioning

confidence: 99%

The p53 activation and apoptosis induced by DNA damage are reversibly inhibited by salicylate

Chernov

Stark

1997

Oncogene

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“…LMPCR was performed on the enzyme-treated DNA as described (34). Oligonucleotide primers for LMPCR were as follows: 5Ј-CAAAA-AAGGGAATAAGG-3Ј (supF-1), 5Ј-CTTAGCTTTCGCTAAGG-3Ј (supF-4), 5Ј-TAAGGGCGACACGGAAAT-3Ј (supF-2), 5Ј-TCGCTAAGGATCC-GGGT-3Ј (supF-5), 5Ј-GAAATGTTGAATACTCATACTCTTCC-3Ј (supF-3), 5Ј-AAGGATCCGGGTACCGAA-3Ј (supF-6).…”

Section: Ligation-mediated Pcr (Lmpcr)-based Deaminationmentioning

confidence: 99%

“…The oligonucleotide linker, consisting of a 25-mer annealed to an 11-mer oligonucleotide, was then ligated to the blunt-ended, primer-extended molecules. After ligation and precipitation of the DNA, gene-specific DNA fragments were amplified with Taq polymerase (Roche Molecular Biochemicals) by using the 25-mer of the linker and a gene-specific PCR primer (primer supF-2 or supF-5) under conditions given previously (34). After 21 cycles of PCR, the samples were phenol/chloroform-extracted and ethanol-precipitated, and the amplified fragments were separated on 8% (w/v) polyacrylamide gels containing 7 M urea.…”

Section: Ligation-mediated Pcr (Lmpcr)-based Deaminationmentioning

confidence: 99%

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Deamination of 5-Methylcytosines within Cyclobutane Pyrimidine Dimers Is an Important Component of UVB Mutagenesis

Lee

Pfeifer

2003

Journal of Biological Chemistry

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UVB mutagenesis is characterized by an abundance of C 3 T and 5-methylcytosine 3 T transitions at dipyrimidine sequences. It is not known how these mutations might arise. One hypothesis is that UV-induced mutations occur only after deamination of the cytosine or 5-methylcytosine within the pyrimidine dimer. It is not clear how methylation of cytosines at the 5-position influences deamination and how this affects mutagenesis. We have now conducted experiments with a CpG-methylated supF shuttle vector that was irradiated with UVB and then incubated at 37°C to allow time for deamination before passage through a human cell line to establish mutations. This led to a significantly increased frequency of CC 3 TT mutations and of transition mutations at 5-PymCG-3 sequences. A spectrum of deaminated cis-syn cyclobutane pyrimidine dimers in the supF gene was determined using the mismatch glycosylase activities of MBD4 protein in combination with ligation-mediated PCR. Methylation at the C-5 position promoted the deamination of cytosines within cis-syn cyclobutane pyrimidine dimers, and these two events combined led to a significantly increased frequency of UVB-induced transition mutations at 5-PymCG-3 sequences. Under these conditions, the majority of all supF mutations were transition mutations at 5-PymCG-3, and they clustered at several mutational hot spots. Exactly these types of mutations are frequently observed in the p53 gene of nonmelanoma skin tumors. This particular mutagenic pathway may become prevalent under conditions of inefficient DNA repair and slow proliferation of cells in the human epidermis.The UV component of sunlight is responsible for the induction of skin tumors, most notably basal cell and squamous cell carcinomas and most likely also melanomas (1, 2). The most frequent UV-induced mutations are C 3 T or CC 3 TT mutations involving pyrimidine dinucleotide sequences. These mutations are considered as a characteristic fingerprint that can be ascribed to solar UV irradiation (3). Such mutations are often found in the p53 gene of sunlight-associated skin cancers (4, 5).The two most abundant UV-induced DNA photoproducts are the cis-syn cyclobutane pyrimidine dimers (CPDs) 1 and the pyrimidine (6 -4) pyrimidone photoproducts ((6 -4)-photoproducts). Most of the mutagenic and carcinogenic action of sunlight has been attributed to the UVB portion of the solar spectrum (6), with a possible, but controversial, role for UVA (320 -400 nm) in the induction of melanoma (7). The CPD is considered the most important UV-induced lesion based on its relatively high abundance, slow repair, and known mutagenicity (8 -11).In an attempt to dissect the individual contributions of CPDs and (6 -4)-photoproducts to UVB mutagenesis, we have previously introduced foreign photolyase genes into a mouse cell line that carries two transgenic mutation reporter genes. We studied the mutations produced after photoproduct-specific photoreactivation and showed that the CPD is responsible for a great majority of the mutations induced by U...

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“…Cette technique est également fréquemment utilisée pour examiner de près d'autres phénomènes concernant notamment la répa-ration des dommages, le fait qu'un brin soit transcrit ou non (réparation couplée à la transcription) [4], l'éloi-gnement d'une région par rapport au promoteur [33] ou encore le rôle exercé par différentes protéines sur certains aspects précis de la réparation [34,35]. ‡…”

Section: Resultsunclassified

Comprendre la mutagenèse somatique grâce à la cartographie des dommages à l’ADN

2010

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L'ADN des cellules est constamment endommagé par des stress endogènes comme les espèces oxygénées réacti-ves produites par le métabolisme cellulaire, et par des stress exogènes tels que les ultraviolets (UV) [1]. Ces altérations peuvent mener à des mutations, c'est-à-dire à des modifications de l'information génétique codée par la molécule. Certains changements dans l'information génétique des cellules somatiques (mutations ponctuelles et/ou réarrangements chromosomiques) sont une cause première de transformation maligne des cellules. L'accumulation de ces altérations dans des gènes importants qui jouent un rôle dans le maintien de l'intégrité cellulaire, tel le contrôle du cycle cellulaire, la réparation et l'apoptose, peut entraîner la multiplication anarchique de cellules anormales et la formation d'une tumeur. Afin d'expliquer la relation qui existe entre les dommages à l'ADN, les mutations et la formation des tumeurs, on se fonde sur la théorie de la mutagenèse somatique énoncée par Thilly en 1983 [2] puis amé-liorée par Holmquist et Gao en 1997 [3]. Cette théorie tente de pré-dire la probabilité qu'a un dommage causé par un agent mutagène d'aboutir à la transformation maligne d'une cellule. Plusieurs facteurs interviennent successivement dans la mutagenèse somatique : (1) la fréquence des dommages, (2) la vitesse de leur réparation, (3) le comportement de la polymérase lors de la réplication de l'ADN endommagé et (4) la sélection des mutations « avantageuses » (Figure 1). > La théorie de la mutagenèse somatique indique que la transformation maligne des cellules est intimement liée à la formation de dommages à l'ADN et au risque que ces derniers puissent mener à des mutations favorables à la croissance cellulaire anarchique. Elle énonce le lien logique qui associe le cancer à l'exposition à des agents génotoxiques. Les spectres de mutations, notamment dans le gène p53, recensent les mutations dans un type de cancer donné en fonction de leur position nucléotidique. Les positions les plus fréquemment mutées sont différentes selon les cancers et reflètent donc la signature du ou des agents mutagènes qui en sont à l'origine. La technologie LMPCR (ligation-mediated PCR) permet de cartographier au niveau nucléotidique les sites les plus fréquemment endommagés par un agent génotoxique donné. Ainsi, on a la possibilité de chercher une corrélation entre ces sites fréquemment endommagés et les sites fréquem-ment mutés dans un type de cancer. Cela a été notamment appliqué pour confirmer à l'échelle moléculaire le lien étiologique reliant une exposition aux UVB au cancer de la peau, ainsi que celui qui s'établit entre plusieurs substances de la fumée de tabac et le cancer du poumon. < R. Drouin : Service de génétique, Département de pédiatrie, local 1428, Faculté de médecine et des sciences de la santé,

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DNA repair domains within a human gene: selective repair of sequences near the transcription initiation site.

Cited by 111 publications

References 52 publications

The p53 activation and apoptosis induced by DNA damage are reversibly inhibited by salicylate

The p53 activation and apoptosis induced by DNA damage are reversibly inhibited by salicylate

Deamination of 5-Methylcytosines within Cyclobutane Pyrimidine Dimers Is an Important Component of UVB Mutagenesis

Comprendre la mutagenèse somatique grâce à la cartographie des dommages à l’ADN

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