The present disclosure belongs to the field of biomedicine. Specifically, the present disclosure relates to a circular RNA molecule, a cyclization precursor RNA molecule, a recombinant nucleic acid molecule, a recombinant expression vector, a recombinant host cell, a composition and use thereof in targeted degradation of a protein of interest, as well as a method for preventing or treating a disease. The circular RNA molecule has good membrane permeability, is easily delivered into cells, and has high-efficiency in vivo protein targeted degradation activity. The circular RNA molecule of the present disclosure successfully achieves inhibition of tumor growth, which proves the in vivo protein degradation activity of bio-PROTACs for the first time, and provides a positive and effective treatment solution for the treatment of diseases such as tumor.

The invention provides an improved host strain for production of desired protein.

This invention relates to a plant E3 ubiquitin ligase (termed DA2) which acts synergistically with DA1 to control seed and organ size. Methods of increasing plant yield are provided that comprise reducing the expression or activity of DA2 in a plant that is deficient in DA1 expression or activity. Plants with increased yield and methods of producing such plants are also provided.

The invention relates to compositions including polynucleotides encoding polypeptides which have been chemically modified by replacing the uridines with 1-methyl-pseudouridine to improve one or more of the stability and/or clearance in tissues, receptor uptake and/or kinetics, cellular access by the compositions, engagement with translational machinery, mRNA half-life, translation efficiency, immune evasion, protein production capacity, secretion efficiency, accessibility to circulation, protein half-life and/or modulation of a cell's status, function, and/or activity.

Angelman Syndrome (AS) is a genetic disorder occurring in approximately one in every 15,000 births. It is characterized by severe mental retardation, seizures, difficulty speaking and ataxia. The gene responsible for AS was discovered to be UBE3A and encodes for E6-AP, an ubiquitin ligase. A unique feature of this gene is that it undergoes maternal imprinting in a neuron-specific manner. In the majority of AS cases, there is a mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental disomy or mismethylation of the maternal gene. While most human disorders characterized by severe mental retardation involve abnormalities in brain structure, no gross anatomical changes are associated with AS. We have generated a Ube3a protein with additional sequences that should allow the secretion from cells and uptake by neighboring neuronal cells. This would confer a functional E6-AP protein into the neurons and rescue disease pathology.

The present invention relates to an isolated chimeric molecule comprising a degradation domain including a eukaryotic U-box motif and a targeting domain capable of immunospecifically directing the degradation domain to a substrate where the targeting domain is heterologous to the degradation domain. A linker couples the degradation domain to the targeting domain. Also disclosed are compositions as well as methods of treating a disease, substrate silencing, screening agents for therapeutic efficacy against a disease, and methods of screening for disease biomarkers.

The present disclosure relates to compounds for activating the enzymatic activity of an E3 ubiquitin ligase and methods for treating a disease or disorder in a subject with diminished E3 ubiquitin ligase enzymatic activity. In some embodiments, the present disclosure provides a compound of Formula I

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or a compound of Formula II.

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or pharmaceutically acceptable salts thereof.

This invention relates to a plant E3 ubiquitin ligase (termed DA2) which acts synergistically with DA1 to control seed and organ size. Methods of increasing plant yield are provided that comprise reducing the expression or activity of DA2 in a plant that is deficient in DA1 expression or activity. Plants with increased yield and methods of producing such plants are also provided.

Certain embodiments are directed to methods and compounds for inhibiting UBE3A-ATS, the endogenous antisense transcript of ubiquitin protein ligase E3A (UBE3A). Such methods and compounds are useful for. Several embodiments provided herein relate to the discovery that antisense compounds targeting UBE3A-ATS induce paternal expression of UBE3A. Several embodiments are drawn to methods and compounds for inducing paternal expression of UBE3A using antisense compounds targeting UBE3A-ATS within a region of UBE3A-ATS that includes the sequence of the small nucleolar RNA (snoRNA), HBII-85 (also referred to as SNORD116).

The invention provides methods and compositions for enhancing the efficacy of cancer therapies through modulation of BAL1 and/or BBAP. Also provided are methods for predicting the efficacy of cancer therapies or treating cancer in a subject through modulation of BAL1 and/or BBAP. Further provided are methods for identifying compounds that are capable of modulating BAL1-BBAP complexes.