Domain-specific p53 mutants activate EGFR by distinct mechanisms exposing tissue-independent therapeutic vulnerabilities.

Mis-sense mutations affecting TP53 promote carcinogenesis both by inactivating tumor suppression, and by conferring pro-carcinogenic activities. We report here that p53 DNA-binding domain (DBD) and transactivation domain (TAD) mis-sense mutants unexpectedly activate pro-carcinogenic epidermal growth factor receptor (EGFR) signaling via distinct, previously unrecognized molecular mechanisms. DBD- and TAD-specific TP53 mutants exhibited different cellular localization and induced distinct gene expression profiles.

Rapid recruitment of p53 to DNA damage sites directs DNA repair choice and integrity.

SignificanceOur work focuses on the critical longstanding question of the nontranscriptional role of p53 in tumor suppression. We demonstrate here that poly(ADP-ribose) polymerase (PARP)-dependent modification of p53 enables rapid recruitment of p53 to damage sites, where it in turn directs early repair pathway selection. Specifically, p53-mediated recruitment of 53BP1 at early time points promotes nonhomologous end joining over the more error-prone microhomology end-joining.

Trikoramide A, a Prenylated Cyanobactin from the Marine Cyanobacterium .

A new cyclic decapeptide, trikoramide A (), has been isolated from samples of the marine cyanobacterium , collected from Bintan Island, Indonesia. Trikoramide A () is a C-prenylated cyclotryptophan-containing cyanobactin. Its planar structure was deduced by 1D and 2D NMR spectroscopy as well as HR-MS/MS data.

Draft Genome Sequence of sp. Strain 007/AIA-02/001, Isolated from the Marine Sponge .

We report the draft genome sequence of a marine bacterium, sp. strain 007/AIA-02/001, isolated from the marine sponge , obtained from water off the coast of Singapore. The analysis of the bacterial genome using the bioinformatics tool antiSMASH 4.

Integrated Genomic and Metabolomic Approach to the Discovery of Potential Anti-Quorum Sensing Natural Products from Microbes Associated with Marine Samples from Singapore.

With 70% of the Earth's surface covered in water, the marine ecosystem offers immense opportunities for drug discovery and development. Due to the decreasing rate of novel natural product discovery from terrestrial sources in recent years, many researchers are beginning to look seaward for breakthroughs in new therapeutic agents. As part of an ongoing marine drug discovery programme in Singapore, an integrated approach of combining metabolomic and genomic techniques were initiated for uncovering novel anti-quorum sensing molecules from bacteria associated with subtidal samples collected in the Singapore Strait.

Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity.

Chemotoxicity due to unwanted p53 activation in the bone marrow remains an unmet clinical challenge. Doxorubicin, a first-line chemotherapy drug, often causes myelosuppression in patients, thus limiting its effectiveness. In this study, we discovered that C646, a reversible p300 inhibitor, downregulates p53 transcription and selectively protects noncancerous cells from p53-dependent apoptosis.

Protein and Protease Sensing by Allosteric Derepression.

Peptide motifs are crucial mediators of protein-protein interactions as well as sites of specific protease activity. The detection and characterization of these events is therefore indispensable for a detailed understanding of cellular regulation. Here, we present versatile and modular sensors that allow the user to detect protease activity and protein-peptide interactions, as well as to screen for inhibitors using chromogenic, fluorescent, or luminescent output.

Going native: Complete removal of protein purification affinity tags by simple modification of existing tags and proteases.

Protein purification typically involves expressing a recombinant gene comprising a target protein fused to a suitable affinity tag. After purification, it is often desirable to remove the affinity tag to prevent interference with downstream functions of the target protein. This is mainly accomplished by placing a protease site between the tag and the target protein.