J. Robert Hogg, Ph.D.

The Laboratory of Ribonucleoprotein Biochemistry, led by Dr. J. Robert Hogg, studies how RNA-protein interactions control messenger RNA stability. A major focus is nonsense-mediated mRNA decay (NMD), an RNA quality-control and gene-regulatory pathway.

Research Interests

Gene expression depends on both the synthesis and degradation of messenger RNAs (mRNAs). Our goal is to understand how RNA-binding proteins and RNA decay factors determine which mRNAs are destroyed, when they are destroyed, and how rapidly they decay.

Much of our work focuses on NMD, which degrades many mRNAs containing premature termination codons while also regulating normal cellular transcripts. We combine biochemical and biophysical experiments with cell-based and transcriptome-wide approaches to understand how NMD selects its targets and how RNA-protein interactions determine mRNA lifetimes.

How are individual transcripts selected for NMD?

Many normal mRNAs contain features that are associated with NMD sensitivity but nevertheless escape degradation. We have found that sequence-specific RNA-binding proteins, including PTBP1 and hnRNP L, can protect transcripts from NMD by promoting dissociation of the NMD factor UPF1 from potential substrates. These findings suggest that NMD substrate selection reflects competition among decay factors, protective RNA-binding proteins, and the translation machinery.

How do the properties of UPF1 control NMD?

UPF1 is an RNA helicase that binds RNA with little sequence specificity. Our work has shown that the dynamics of UPF1-RNA interactions are critical for NMD. ATP hydrolysis promotes UPF1 dissociation from RNA, and proteins such as PTBP1 can exploit this activity to protect transcripts from decay. UPF1 proteins with strongly impaired helicase and translocation activities can nevertheless support efficient NMD, indicating that regulation of RNA binding is more important than helicase activity itself.

More recently, we found that changing the rates of UPF1 binding to and dissociation from RNA in either direction impairs NMD. These results support a “butterfly” model in which efficient NMD requires a balance between stable engagement with potential substrates and rapid dissociation that allows UPF1 to sample many RNAs.

UPF1 activity also changes with cellular conditions. Most human cells express two UPF1 isoforms that differ in a short regulatory loop. The less abundant isoform with an extended regulatory loop has distinct biochemical properties and remains active on a subset of transcripts when translation is partially repressed. Alternative UPF1 isoforms can therefore reprogram NMD specificity in response to changes in cellular physiology.

Why do different transcripts undergo NMD with different efficiencies?

RNA abundance reflects both RNA synthesis and degradation, so direct measurements of RNA decay are needed to understand post-transcriptional regulation. We have used approaches combining metabolic RNA labeling, nucleotide-recoding RNA sequencing, and computational modeling to measure degradation rates at transcript-isoform resolution.

These studies reveal substantial differences in NMD efficiency among transcripts. Premature termination codon-containing transcripts are not uniformly degraded, and some transcripts without canonical premature termination codons undergo rapid NMD-dependent decay. These findings suggest that NMD efficiency is a continuum rather than a simple distinction between targets and non-targets.

We are using these approaches to identify the molecular features that determine RNA decay rates and to connect transcriptome-wide measurements of RNA stability with mechanistic studies of RNA-protein interactions.

J. Robert Hogg graduated from Haverford College in 2000 with a B.S. in biology and earned a Ph.D. from the Department of Molecular and Cell Biology at the University of California, Berkeley in 2006. His thesis research at UC Berkeley focused on the composition and function of ribonucleoprotein complexes containing noncoding RNAs. He pursued postdoctoral research at Columbia University, where he studied mechanisms of mRNA biogenesis and quality control. He joined the NHLBI in 2011 as an Earl Stadtman tenure-track Investigator and became a Senior Investigator in 2019.