Returning value to the community through the All of Us Research Program Data Sandbox model.

Objective: The All of Us Research Program aims to return value to participants by developing research capacity in communities. We describe a novel set of introductory exercises (Data Sandboxes) and specialized trainings to orient researchers to the Researcher Workbench to foster health equity research.

Materials And Methods: We developed a tailored training to familiarize researchers with the All of Us Research Program: (1) orientation, (2) tailored "data treasure hunt" using the Public Data Browser, and (3) overview of the analyses tools and platform.

Tau: More than a microtubule-binding protein in neurons.

Tau protein was discovered as a microtubule-associated protein nearly 50 years ago, and our understanding of tau has revolved around that role. Even with tau's rise to stardom as a central player in neurodegenerative disease, therapeutic efforts have largely been targeted toward cytoskeletal changes. While some studies hinted toward non-cytoskeletal roles for tau, it is only fairly recently that these ideas have begun to receive considerable attention.

Poly(A) tail dynamics: Measuring polyadenylation, deadenylation and poly(A) tail length.

Transcription of mRNAs culminates in RNA cleavage and a coordinated polyadenylation event at the 3' end. In its journey to be translated, the resulting transcript is under constant regulation by cap-binding proteins, miRNAs, and RNA binding proteins, including poly(A) binding proteins (PABPs). The interplay between all these factors determines whether nuclear or cytoplasmic exoribonucleases will gain access to and remove the poly(A) tail, which is so critical to the stability and translation capacity of the mRNA.

Connections between 3' end processing and DNA damage response: Ten years later.

Ten years ago we reviewed how the cellular DNA damage response (DDR) is controlled by changes in the functional and structural properties of nuclear proteins, resulting in a timely coordinated control of gene expression that allows DNA repair. Expression of genes that play a role in DDR is regulated not only at transcriptional level during mRNA biosynthesis but also by changing steady-state levels due to turnover of the transcripts. The 3' end processing machinery, which is important in the regulation of mRNA stability, is involved in these gene-specific responses to DNA damage.

Nucleolin phosphorylation regulates PARN deadenylase activity during cellular stress response.

Nucleolin (NCL) is an abundant stress-responsive, RNA-binding phosphoprotein that controls gene expression by regulating either mRNA stability and/or translation. NCL binds to the AU-rich element (ARE) in the 3'UTR of target mRNAs, mediates miRNA functions in the nearby target sequences, and regulates mRNA deadenylation. However, the mechanism by which NCL phosphorylation affects these functions and the identity of the deadenylase involved, remain largely unexplored.

Poly(A) binding proteins: are they all created equal?

The PABP family of proteins were originally thought of as a simple shield for the mRNA poly(A) tail. Years of research have shown that PABPs interact not only with the poly(A) tail, but also with specific sequences in the mRNA, having a general and specific role on the metabolism of different mRNAs. The complexity of PABPs function is increased by the interactions of PABPs with factors involved in different cellular functions.

DNA damage-induced BARD1 phosphorylation is critical for the inhibition of messenger RNA processing by BRCA1/BARD1 complex.

BRCA1-associated RING domain protein BARD1, along with its heterodimeric partner BRCA1, plays important roles in cellular response to DNA damage. Immediate cellular response to genotoxic stress is mediated by a family of phosphoinositide 3-kinase-related protein kinases, such as ataxia-telangiectasia mutated (ATM), ATM and Rad3-related, and DNA-dependent protein kinase. ATM-mediated phosphorylation of BRCA1 enhances the DNA damage checkpoint functions of BRCA1, but how BARD1 is regulated during DNA damage signaling has not been examined.