Disclosed herein are conditional siRNAs activatable by CBF-MYH11 oncogenic gene and use thereof for treating conditions such as acute myeloid leukemia (AML). The conditional siRNAs target MCL-1 or HDAC8.

Engineered CRISPR-Cas9 nucleases with improved specificity and their use in genomic engineering, epigenomic engineering, genome targeting, and genome editing.

Compositions and methods for assessing protein function are provided. A modified SpyCatcher protein that can include a tag is provided. Modified SpyCatcher proteins linked to a protein of interest, such as a nuclease are also provided. The methods include contacting a SpyCatcher protein and a SpyTagged protein to form a complex that may further include a protein of interest, one or more nucleic acids, and/or a nuclease. The methods can be used to purify a protein of interest or identify or target a protein binding site in a nucleic acid.

The instant invention provides workflows for the design and characterization of mechanism-based sirtuin modulating compounds, including new or improved sirtuin activating compounds. Workflows for the design of mechanism-based sirtuin activating compounds are provided, based on conditions that must be satisfied by activators if they are to exploit the common catalytic mechanism of all sirtuin enzymes and hence increase catalytic efficiency for any sirtuin and any substrate.

Provided is a compound that comprises the structure:

##STR00001##

where SIG is a signaling molecule and R.sup.3 is a formyl, a succinyl, a methyl succinyl, or a myristoyl. Also provided is a kit is provided that comprises the above compound, with instructions for determining the presence of the enzyme. Additionally, a method is provided for determining whether a sample has an enzyme that removes a succinyl, a methyl succinyl, a formyl, or a myristoyl moiety from an -amino of a lysine. Also provided is a method of determining whether a molecule inhibits an enzyme that removes a succinyl, a methyl succinyl, a formyl, or a myristoyl moiety from an -amino of a lysine.

The present disclosure provides for methods and compositions for treating cancer. A subject having lymphoma is administered an EZH2 inhibitor and an HDAC inhibitor. The combination of the EZH2 inhibitor and the HDAC inhibitor produces a synergistic effect on the cancer compared to the effect of the EZH2 inhibitor or the HDAC inhibitor alone.

Isolated polynucleotides and polypeptides, and recombinant DNA constructs are useful for conferring improved drought tolerance. Compositions (such as plants or seeds) comprising these recombinant DNA constructs; and methods utilizing these recombinant DNA constructs. The recombinant DNA constructs comprise a polynucleotide operably linked to a promoter that is functional in a plant, wherein said polynucleotides encode drought tolerance polypeptides.

The invention provides a method of selecting a mutant polypeptide having lysine demodification, in particular lysine deacylation, activity, wherein the method comprises the following steps (a) incubating a mutant polypeptide having an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 1 with a peptide or polypeptide comprising an inactivated essential lysine residue; and (b) determining the activity of the mutant polypeptide to activate the peptide or polypeptide comprising the inactivated essential lysine residue, wherein the mutant polypeptide and the peptide or polypeptide comprising an inactivated essential lysine residue are incubated in a biological cell. The invention furthermore relates to an acylated luciferase, particularly Firefly luciferase, and uses thereof. The present invention furthermore relates to a mutant polypeptide comprising an amino acid sequence having at least 98% sequence homology with SEQ ID NOs: 2, 3, 4, 5 or 6 and having lysine demodification, in particular lysine deacylation, activity, wherein the mutant polypeptide is not identical to SEQ ID NO: 1. The invention also relates to the mutant polypeptide of the invention and a peptide or polypeptide comprising an inactivated essential lysine residue for use in treating cancer.

The present application provides a HDAC6 inhibitor for use in treating a degenerative disease associated with the formation of intracellular granules, wherein said granules are formed by the aggregation of a protein selected from the group comprising APP, Tau, Ataxin-2, hnRNPA1, C9orf72, Lamin A/C, Myotilin, Matrin 3, alpha-synuclein, SOD1, FUS, hnRNPA2B1, VCP, TIA1, Desmin and Huntingtin, and wherein said inhibitor inhibits both the CD1 and CD2 of HDAC6.

The present application provides a recombinant binding protein that specifically binds to HDAC6 and blocks the ubiquitin-engaging zinc finger domain of HDAC6.