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Structure of p53 binding to the BAX response element reveals DNA unwinding and compression to accommodate base-pair insertion.

ABSTRACT: The p53 core domain binds to response elements (REs) that contain two continuous half-sites as a cooperative tetramer, but how p53 recognizes discontinuous REs is not well understood. Here we describe the crystal structure of the p53 core domain bound to a naturally occurring RE located at the promoter of the Bcl-2-associated X protein (BAX) gene, which contains a one base-pair insertion between the two half-sites. Surprisingly, p53 forms a tetramer on the BAX-RE that is nearly identical to what has been reported on other REs with a 0-bp spacer. Each p53 dimer of the tetramer binds in register to a half-site and maintains the same protein-DNA interactions as previously observed, and the two dimers retain all the protein-protein contacts without undergoing rotation or translation. To accommodate the additional base pair, the DNA is deformed and partially disordered around the spacer region, resulting in an apparent unwinding and compression, such that the interactions between the dimers are maintained. Furthermore, DNA deformation within the p53-bound BAX-RE is confirmed in solution by site-directed spin labeling measurements. Our results provide a structural insight into the mechanism by which p53 binds to discontinuous sites with one base-pair spacer.

SUBMITTER: Chen Y

PROVIDER: S-EPMC3783167 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Structure of p53 binding to the BAX response element reveals DNA unwinding and compression to accommodate base-pair insertion.

Chen Yongheng Y Zhang Xiaojun X Dantas Machado Ana Carolina AC Ding Yuan Y Chen Zhuchu Z Qin Peter Z PZ Rohs Remo R Chen Lin L

Nucleic acids research 20130708 17

The p53 core domain binds to response elements (REs) that contain two continuous half-sites as a cooperative tetramer, but how p53 recognizes discontinuous REs is not well understood. Here we describe the crystal structure of the p53 core domain bound to a naturally occurring RE located at the promoter of the Bcl-2-associated X protein (BAX) gene, which contains a one base-pair insertion between the two half-sites. Surprisingly, p53 forms a tetramer on the BAX-RE that is nearly identical to what ...[more]

PMID: 23836939

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Project description:Worldwide, thalassemia represents one of the most common genetic disorders. There is a prevalence of Beta-thalassemia in Kingdom of Saudi Arabia (KSA), however there is a genetic counseling availability and an existence of mandatory premarital testing policy. Few studies detect molecular mutations of thalassemia genes in different KSA governates, including Makkah, Hufuf, Qatif, and Dammam but in our peer knowledge there is no reports on high altitude Taif region. The aim of the present study is to evaluate the molecular mutation analysis of β-thalassemia gene in El Taif province (as a high-altitude area) patients of KSA and to estimate the iron overload toxicity due to thalassemia syndrome on the hotspot noncoding D-loop region (hypervariable, HV2 gene fragment) of mtDNA. Blood samples were collected from total 25 β-thalassemia patients and 25 normal control that were used for HPLC, hematological analysis and different molecular evaluations. Extracted nuclear DNA from blood sample was used to detect known mutations accompanied with β-thalassemia in other countries using PCR-ARMS technique targeting IVSII-1, IVSI-5, Codon 8/9, Cd44 and Cd5 genes' mutations. Moreover, mtDNA was used to detect point of mutation of HV2 fragment in the D-loop region using PCR-SSCP and then sequencing. Results show significant increase in the level of HbA2 and decrease of HbA in comparison to control by using HPLC. PCR-ARMS reports that all β-thalassemia patients have heterozygous alleles of wild and mutated regions with nucleotide transition/transversion of IVSI-5 (AC>AG), Codon 8/9 (CT>CC), and Cd44 (GG>GA), however no point of mutation was detected in IVSII-1 (AC>AT) Cd5 (CT>CG) genes. Moreover, PCR-SSCP shows points of mutations for β-thalassemia HV2 fragment that were confirmed by sequencing in the form of base pairs deletion, insertion and transition/transversion. For the first time, the present study reports the presence of 2 bps found in HV2 region that might be specific to KSA nations and not found in other countries. In conclusion, our results were in concurrent with other studies in the presence of specific genetic mutations in β-thalassemia patients that is accompanied with points of mutations in HV2 region of high altitude Taif governate.

Dataset Information

Structure of p53 binding to the BAX response element reveals DNA unwinding and compression to accommodate base-pair insertion.

Publications

Structure of p53 binding to the BAX response element reveals DNA unwinding and compression to accommodate base-pair insertion.

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