p53 binds single-stranded DNA ends through the C-terminal domain and internal DNA segments via the middle domain

Bakalkin, Georgy; Selivanova, Galina; Yakovleva, Tatjana; Киселева, Елена; Kashuba, Elena; Magnússon, Kristinn P.; Szekeres, L.; Klein, George; Terenius, Lars; Wiman, Klas G.

doi:10.1093/nar/23.3.362

Cited by 151 publications

(109 citation statements)

References 25 publications

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“…These properties led to the suggestion that p53 represses DNA replication by inhibiting the unwinding of the DNA at replication origins. Such a function is also in keeping with the observation that p53 can promote DNA or RNA re-annealing, a reaction which opposes the unwinding (Oberosler et al, 1993;Bakalkin et al, 1994Bakalkin et al, , 1995Brain and Jenkins, 1994. p53 is normally expressed at a very low level (Crawford et al, 1981;Benchimol et al, 1982;May et al, 1991). Most of the results implicating p53 in either transcription or replication were obtained using in vitro systems in which p53 was over-expressed, thus representing non-physiological conditions.…”

Section: Introductionsupporting

confidence: 67%

A functional analysis of p53 during early development of xenopus laevis

et al. 1997

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p53 is a nuclear protein that acts like a tumor suppressor and is involved in regulation of cellular growth. In Xenopus, the p53 protein is highly expressed during oogenesis and is strictly cytoplasmic in the oocyte. We have analysed its participation in DNA replication and transcription during early development, using the egg and oocyte as model-systems. The injection of sperm nuclei into Xenopus eggs is followed by DNA replication and mitotic events. We show that the endogenous p53 enters the nuclei and moves through a series of discrete subnuclear loci whose distribution is S-phase speci®c. A speci®c peripheral nuclear localization of p53 is observed before entry into S-phase, followed by an internal localization which is strictly dependent on ongoing DNA synthesis. At no stage in the cell cycle, however, did we observe any co-localization with RPA or PCNA, which were used as initiation or elongation markers for DNA replication. We also show that injection into the nucleus of the oocyte of small amounts of either Xenopus or human p53 ± less than 10% of the cytoplasmic storage ± is su cient to block RNA polymerase IIdependent transcription from a coinjected TATA-boxcontaining reporter plasmid. Transcription is rescued by microinjection of the TATA-box binding protein (TBP), suggesting that nuclear exclusion of p53 during oogenesis may be necessary for transcription of maternal genes. These characteristics are discussed in relation to the regulation of nuclear activities during early embryogenesis.

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Section: Introductionsupporting

confidence: 67%

A functional analysis of p53 during early development of xenopus laevis

et al. 1997

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“…The results are presented in Figure 5a and show that there is a good correlation between the capacity of a single-stranded oligonucleotide to form a stem-loop structure and its ability of being bound by p53: Binding was observed only with those single stranded DNAs (RGC-1a, RGC-2 and RGC-du) that were capable of intrastrand base pairing and formation of a stem-loop structure (Figure 5a, lanes 1 ± 6). The observed binding was not due to the ability of p53 to nonspeci®cally bind single stranded DNA through its C-terminus (Bakalkin et al, 1994(Bakalkin et al, , 1995, as p53 failed to bind single stranded RGC-1b DNA that lacks any internal symmetry, and therefore does not have the potential for intrastrand base pairing (lanes 7 and 8). The failure of p53 to bind single-stranded RGC-1b DNA was not due to an improper sequence arrangement, because this DNA was e ciently and speci®cally bound by p53 after annealing with its complementary strand (Figure 2, lanes 3 and 4, RGC-1b/ds).…”

Section: Comparative Analysis Of Natural P53 Binding Sitesmentioning

confidence: 99%

DNA-conformation is an important determinant of sequence-specific DNA binding by tumor suppressor p53

1997

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Sequence-speci®c transactivation of target genes is one of the most important molecular properties of the tumor suppressor p53. Binding of p53 to its target DNAs is tightly regulated, with modi®cations in the carboxyterminal regulatory domain of the p53 protein playing an important role. In this study we examined the possible in¯uence of DNA structure on sequence-speci®c DNA binding by p53, by analysing its binding to p53 consensus elements adopting di erent conformations. We found that p53 has the ability to bind to consensus elements which are present in a double-helical form, as well as to consensus elements which are located within alternative non-B-DNA structures. The ability of a consensus element to adopt either one of these conformations is dependent on its sequence symmetry, and is strongly in¯uenced by its sequence environment. Our data suggest a model according to which the conformational status of the target DNA is an important determinant for sequence-speci®c DNA binding by p53. Modi®cations in the carboxy-terminal regulatory region of p53 possibly determine the preference of p53 for a given DNA conformation.

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“…Upon treatment of reagents that damage DNA, p53 protein levels increase. Its C-terminal domain bind directly to the damaged DNA, allowing repair processes to initiate (Bakalkin et al, 1994(Bakalkin et al, , 1995. p53 also activates its target genes such as p21, a CDK inhibitor, to prevent cells that contain damaged DNA from proliferating el-Deiry et al, 1993el-Deiry et al, , 1994Harper et al, 1993;Waga et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

A targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability

et al. 1998

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Germline mutations of the Brca1 gene are responsible for most cases of familial breast and ovarian cancers, but somatic mutations are rarely detected in sporadic events. Moreover, mouse embryos de®cient for Brca1 have been shown to die during early embryogenesis due to a proliferation defect. These ®ndings seem incompatible with the tumor suppress function assigned to this gene and raise questions about the mechanism by which Brca1 mutations cause tumorigenesis. We now directly demonstrate that BRCA1 is responsible for the integrity of the genome. Murine embryos carrying a Brca1 null mutation are developmentally retarded and hypersensitive to girradiation, suggesting a failure in DNA damage repair. This notion is supported by spectral karyotyping (SKY) of metaphase chromosomes, which display numerical and structural aberrations. However, massive chromosomal abnormalities are only observed when a p53 7/7 background is introduced. Thus, a p53 dependent cell cycle checkpoint arrests the mutant embryos and prevents the accumulation of damaged DNA. Brca1 7/7 ®broblasts are not viable, nor are Brca1 7/7 : p53 7/7 ®broblasts. However, proliferative foci arise from Brca1 7/7 : p53 7/7 cells, probably due to additional mutations that are a consequence of the accumulating DNA damage. We believe that the increased incidence of such additional mutations accounts for the mechanism of tumorigenesis associated with Brca1 mutations in humans.

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p53 binds single-stranded DNA ends through the C-terminal domain and internal DNA segments via the middle domain

Cited by 151 publications

References 25 publications

A functional analysis of p53 during early development of xenopus laevis

A functional analysis of p53 during early development of xenopus laevis

DNA-conformation is an important determinant of sequence-specific DNA binding by tumor suppressor p53

A targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability

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