p53 contains a DNA break-binding motif similar to the functional part of BRCT-related region of Rb

Yamane, Kunio; Katayama, Eisaku; Tsuruo, Takashi

doi:10.1038/sj.onc.1204408

Cited by 7 publications

(3 citation statements)

References 40 publications

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“…The structure of RbN contradicts previous predictions from yeast two hybrid and bioinformatics studies (Bork et al, 1997; Hensey et al, 1994; Yamane et al, 2000; Yamane et al, 2001), which identified two independently folded sub-domains, the more amino-terminal of which was deemed to contain a BRCT-like fold. Our structure shows that the two segments generated by limited proteolysis are in fact intimately interacting parts of a single globular entity, so that interaction studies based on one or other of these in isolation must be viewed with considerable caution.…”

Section: Resultscontrasting

confidence: 77%

Crystal Structure of the Retinoblastoma Protein N Domain Provides Insight into Tumor Suppression, Ligand Interaction, and Holoprotein Architecture

et al. 2007

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The retinoblastoma susceptibility protein, Rb, has a key role in regulating cell-cycle progression via interactions involving the central "pocket" and C-terminal regions. While the N-terminal domain of Rb is dispensable for this function, it is nonetheless strongly conserved and harbors missense mutations found in hereditary retinoblastoma, indicating that disruption of its function is oncogenic. The crystal structure of the Rb N-terminal domain (RbN), reveals a globular entity formed by two rigidly connected cyclin-like folds. The similarity of RbN to the A and B boxes of the Rb pocket domain suggests that Rb evolved through domain duplication. Structural and functional analysis provides insight into oncogenicity of mutations in RbN and identifies a unique phosphorylation-regulated site of protein interaction. Additionally, this analysis suggests a coherent conformation for the Rb holoprotein in which RbN and pocket domains directly interact, and which can be modulated through ligand binding and possibly Rb phosphorylation.

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Section: Resultscontrasting

confidence: 77%

Crystal Structure of the Retinoblastoma Protein N Domain Provides Insight into Tumor Suppression, Ligand Interaction, and Holoprotein Architecture

et al. 2007

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“…This central domain of PARP-1 encompasses a BRCT (BRCA1 C-terminus) motif (aa 372-476) involved in interactions with other proteins, including PARP itself, histones (Buki et al, 1995), XRCC1 (Masson et al, 1998), Oct 1 (Nie et al, 1998), HPV18 E2 (Lee et al, 2002), NF-kB p50 and p65 (Hassa et al, 2001), and p53 (Wesierska-Gadek et al, 2003). Comprising about 100 residues, this BRCT motif is ubiquitous in other proteins involved in DNA repair and cell cycle checkpoints, including XRCC1, DNA ligase III (Nashh et al, 1997), XRCC4, DNA ligase IV (Critchlow et al, 1997), and p53 (Yamane et al, 2001), and represents an interface for multimerization and specific protein-protein contacts between protein pairs. Our results showing that PARP-1 neither binds internal sequences of the E2F-1 promoter nor modifies E2F-1 by poly(ADP-ribosyl)ation is consistent with the fact that PARP-1-E2F-1 binding does not require the DNAbinding domain or the catalytic active site of PARP-1.…”

Section: Discussionmentioning

confidence: 99%

PARP-1 binds E2F-1 independently of its DNA binding and catalytic domains, and acts as a novel coactivator of E2F-1-mediated transcription during re-entry of quiescent cells into S phase

et al. 2003

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The transcription factor E2F-1 is implicated in the activation of S-phase genes as well as induction of apoptosis, and is regulated by interactions with Rb and by cell cycle-dependent alterations in E2F-1 abundance. We earlier demonstrated a pivotal role for poly(ADPribose) polymerase-1 (PARP-1) in the regulation of E2F-1 expression and promoter activity during S-phase re-entry when quiescent cells re-enter the cell cycle. We now investigate the putative mechanism(s) by which PARP-1 may upregulate E2F-1 promoter activity during S-phase re-entry. DNase-1 footprint assays with purified PARP-1 showed that PARP-1 did not directly bind the E2F-1 promoter in a sequence-specific manner. In contrast to p53, a positive acceptor in poly(ADP-ribosyl)ation reactions, E2F-1 was not poly(ADP-ribosyl)ated by wildtype PARP-1 in vitro, indicating that PARP-1 does not exert a dual effect on E2F-1 transcriptional activation. Protein-binding reactions and coimmunoprecipitation experiments with purified PARP-1 and E2F-1, however, revealed that PARP-1 binds to E2F-1 in vitro. More significantly, physical association of PARP-1 and E2F-1 in vivo also occurred in wild-type fibroblasts 5 h after re-entry into S phase, coincident with the increase in E2F-1 promoter activity and expression of E2F-1-responsive Sphase genes cyclin A and c-Myc. Mapping of the interaction domains revealed that full-length PARP-1 as well as PARP-1 mutants lacking either the catalytic active site or the DNA-binding domain equally bind E2F-1, whereas a PARP-1 mutant lacking the automodification domain does not, suggesting that the protein interaction site is located in this central domain. Finally, gel shift analysis with end-blocked E2F-1 promoter sequence probes verified that the binding of PARP-1 to E2F-1 enhances binding to the E2F-1 promoter, indicating that PARP-1 acts as a positive cofactor of E2F-1-mediated transcription.

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“…It recognizes DNA adducts and activates apoptosis [61]. All of them are regulated by p53, which can trigger cell cycle arrest and DNA repair or apoptosis (Figure 1) [62][63][64][65].…”

Section: Introductionmentioning

confidence: 99%

Contribution of genetic factors to platinum-based chemotherapy sensitivity and prognosis of non-small cell lung cancer

Pérez-Ramírez

Cañadas-Garre

Molina

et al. 2017

Mutation Research/Reviews in Mutation Research

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Although platinum-based chemotherapy remains the standard treatment for advanced NSCLC patients, clinical outcomes are poor and most patients develop high-grade toxicities. Genetic factors, such as single nucleotide polymorphisms (SNPs) involved in platinum pharmacodynamics, metabolism and mechanism of action, may account for inter-individual differences shown in effectiveness and toxicity. Polymorphisms in genes involved in DNA repair and others such as PI3K/PTEN/AKT and TGF-β pathways have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with platinum-based chemotherapy. Other cellular processes, like DNA methylation and proliferation have been connected with clinical outcome for platinum-based chemotherapy regimens through folate metabolism and cytokine signaling. The influence of gene polymorphisms in the NER pathway on clinical outcome has been extensively investigated in advanced NSCLC patients treated with platinum-based chemotherapy but contradictory results have been reported. The most recent and thorough meta-analyses have failed to show an association between ERCC1 C118T/C8092A and ERCC5 rs1047768 polymorphisms and response to platinum based chemotherapy. However, other polymorphisms in ERCC2 (Lys751Gln and Asp312Asn) and ERCC5 (rs2094258 and rs2296147) and have been related with overall survival (OS) and progression-free survival (PFS), respectively. The Arg194Trp and Gln399Arg polymorphisms in XRCC1, have also been extensively investigated. Their effects seem to be dependent on ethnicity, and recent meta-analyses have confirmed an association with response in Asian but not in Caucasian patients. The influence on overall response rate (ORR) of the rs861539 polymorphism in XRCC3, part of (DSB) repair pathway, has also been confirmed in a meta-analysis. Finally, SNPs in genes coding proteins of the p53, PI3K, TGF-β, membrane transporters, gluthatione metabolism enzymes and cytokine pathways have been less extensively investigated. Some polymorphisms have been reported to be associated with toxicity or clinical outcome, but data generally come from a limited number of studies and need to be confirmed.

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p53 contains a DNA break-binding motif similar to the functional part of BRCT-related region of Rb

Cited by 7 publications

References 40 publications

Crystal Structure of the Retinoblastoma Protein N Domain Provides Insight into Tumor Suppression, Ligand Interaction, and Holoprotein Architecture

Crystal Structure of the Retinoblastoma Protein N Domain Provides Insight into Tumor Suppression, Ligand Interaction, and Holoprotein Architecture

PARP-1 binds E2F-1 independently of its DNA binding and catalytic domains, and acts as a novel coactivator of E2F-1-mediated transcription during re-entry of quiescent cells into S phase

Contribution of genetic factors to platinum-based chemotherapy sensitivity and prognosis of non-small cell lung cancer

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