RNA regulation
How is RNA regulated by its own structure and poly(ADP-ribose)?
RNA metabolism regulated
by ADP-ribosylation
Since its discovery in 1963, ADP-ribosylation has been implicated in regulating fundamental DNA metabolic processes, including DNA repair, in the nucleus. Little is known about the role of ADP-ribosylation in RNA metabolism or in the cytoplasm. While investigating the role of microRNAs in stress, we previously found that the core microRNA-binding protein Argonaute (Ago) is PARylated and such PARylation reduces microRNA activities. Our recent analyses further revealed that PAR-binding proteins are significantly associated with RNA metabolism, such as splicing and translation. Using novel tools, we are investigating the mechanism of how ADP-ribosylation regulates Argonaute and other RNA-binding proteins.
Leung AK, Vyas S, Rood JE, Bhutkar A, Sharp PA, Chang P. Poly(ADP-ribose) regulates stress responses and microRNA activity in the cytoplasm. Mol Cell. 2011 May 20;42(4):489-99. [Abstract/PDF]
Dasovich M, Beckett MQ, Bailey S, Ong SE, Greenberg MM, Leung AKL. Identifying Poly(ADP-ribose)-Binding Proteins with Photoaffinity-Based Proteomics. J Am Chem Soc. 2021 Mar 3;143(8):3037-3042. [Abstract/PDF]
Structure-mediated RNA decay (SRD) regulated by essential stress granule factor G3BP1
RNA encodes information both in its nucleotide sequence and folded structure. RNA sequence has been determined genome-wide, but most structures remain uncharacterized in cells. We recently made an unexpected discovery that reframes the current understanding of how RNA is degraded. We discovered a pathway that recognizes overall RNA structuredness as a signal for degradation—a new paradigm to read RNA.
This Structure-mediated RNA decay (SRD) requires two double-stranded (ds)RNA binding proteins UPF1, which is central for coordinating mRNA decay pathways, and its associated protein G3BP1. UPF1 cannot regulate highly-structured mRNAs or noncoding RNAs, such as circular RNA, without G3BP1—the essential component of stress granules. Therefore, G3BP1 is the primary regulator of SRD.
Based on computational and experimental analyses, we estimated that this decay pathway regulates one-third of all human genes. We are investigating SRD rules, mechanisms and biology.
Fischer JW, Busa VF, Shao Y, Leung AKL. Structure-Mediated RNA Decay by UPF1 and G3BP1. Mol Cell. 2020 Apr 2;78(1):70-84.e6. [Abstract/PDF]
Our lab research focuses on PAR and RNA—nucleic acids that are critical for gene regulation. This hybrid strategy of investigating two nucleic acids is, perhaps, rooted in the way Dr. Leung was raised in Hong Kong—a city intertwined with British and Chinese heritage.
My best moments in lab meetings are to see my team bouncing ideas back-and-forth between the PAR and RNA worlds — Anthony
Different perspectives, we believe, allow better decisions and innovations.