Alexander Palazzo

Alexander Francis Palazzo was born and raised in Montreal, Canada. As a graduate student in Gregg Gundersen’s laboratory at Columbia University, he discovered two major pathways that regulate cell polarity in migrating fibroblasts. After receiving his PhD in 2003, he moved to Tom Rapoport’s laboratory at Harvard Medical School where he was a Jane Coffin Childs Postdoctoral Fellow. There he investigated how newly synthesized mRNA is exported from the nucleus and then targeted to specific sites in the cytoplasm of mammalian cells, such as the surface of the endoplasmic reticulum. In 2009 he started his lab in the Biochemistry Department. 

Besides his work on mRNA export and localization, Dr. Palazzo is interested in how biological information is extracted from the mammalian genome. He has published several well regarded reviews on how mRNA processing and nuclear export is used to sort useful information from a genome that is mostly filled with junk DNA. 

Nuclear Export and Localization of mRNA 

Gene expression plays a critical role in regulating and modifying various cellular functions, which impact on processes such as development and homeostasis. Gene activation begins in the nucleus, where DNA is transcribed into an RNA nascent transcript that is processed so that non-coding introns are removed by the splicesome, and a cap and poly-A tail are added to the beginning and end of the RNA. Once processing is complete, the mature messenger RNA (mRNA) is exported to the cytoplasm where it localizes to distinct subcellular sites. For example in higher eukaryotes, mRNAs coding for secreted and membrane bound proteins are targeted to the surface of the endoplasmic reticulum (ER). 

Our lab utilizes sophisticated cell manipulation protocols, such as nuclear microinjection, in order to figure out: 

1. How are mRNAs exported from the nucleus? 
2. How are mRNAs localized to their proper subcellular destination, such as the endoplasmic reticulum? 
3. How does mRNA translation in the cytosol differ from translation on the endoplasmic reticulum? 

We have found that certain human mRNAs require high GC-content for their efficient export from the nucleus. We have recently used computational biology to examine evolutionary forces that shape nucleotide content in human genes. In particular we wish to understand:

1. How do adaptive and non-adaptive evolutionary forces shape nucleotide content in human protein-coding genes? 

Nuclear export of mRNA 

We are currently trying to figure out how meaningful information is extracted from our genome, which is mostly comprised of junk DNA. A central player in cellular information processing is the mRNA nuclear export machinery. 

All RNA synthesis occurs in the nucleus. However, it is clear that only certain types of RNA are allowed to be exported to the cytoplasm. We are trying to define: 

1. the rules that dictate whether any given mRNA is exported to the cytoplasm, retained in the nucleus or degraded 
2. the underlying mechanisms that enforce these various fates. 

Ribonucleoprotein complexes 

All RNAs are packaged into larger ribonucleoprotein (RNP) complexes. These complexes may vary considerably between different types of mRNA. The protein component of the RNP dictates where the packaged mRNA is transported, how stable it is, and how efficiently it is translated into protein. We are trying to determine how and where these complexes are assembled and modified throughout the course of an mRNA’s lifetime. 

Our work has indicated that messenger RNPs may be modified after they exit the nucleus through the nuclear pore. We have discovered that one nuclear pore protein, RanBP2/Nup358, directly interacts with mRNAs that encode for secretory proteins. Mutations in this gene have been associated with Acute Necrotizing Encephalopathy 1 (ANE1), a rare condition where cytokines are overproduced in response to viral infection. We are currently investigating whether ANE1-associated mutations alter how RanBP2 interacts with cytokine mRNAs. 

Targeting of mRNAs to the endoplasmic reticulum 

Secretory and membrane-bound proteins are synthesized from mRNAs that are localized to the surface of the endoplasmic reticulum (ER). We have discovered that the ER contains mRNA receptors that aid in this process. We hope to uncover: 

1. the mechanism by which mRNA receptors facilitate ER-association of certain mRNAs 
2. the elements within these mRNAs that determines their targeting to the ER 
3. differences between the composition of cytoplasmic and ER-bound ribonucleoprotein complexes. 

Differences between translation in the cytosol and on the endoplasmic reticulum 

It has been long known that translation in the cytosol and on the surface of the endoplasmic reticulum differ, but the underlying reasons for this are mysterious. We have identified differences between the proteome of cytosolic and endoplasmic reticulum-associated polysomes by mass spectrometry. We are currently investigating how these differences influence mRNA translation in these two compartments. 

Evolution of nucleotide content in genes 

It is generally assumed that the nucleotide content in genes is influenced solely by adaptive evolution, however we have found that certain patterns, such as the peak of GC-content at the start of human protein-coding genes is dictated by historical rates of recombination. 

We are interesting in understanding all the forces that dictate nucleotide content. For the time being we are exploring this using phylogenitic analysis, comparative genomics, and in silico simulations of gene evolution. We aim to understand how these patterns are shaped by adaptive and non-adaptive forces. 

Appointments, Cross Affiliations, Memberships 

2023-2024 — Jean D'Alembert Chair, Université Paris-Saclay 
PLoS One - editorial board member  

Courses Taught 

BCH2207 Collaborative Science: Student Centered Interdisciplinary Studies 
BCH 2115H Applying Modern Evolutionary Thinking to Biochemistry, Cell and Molecular Biology 
BCH473Y Advanced Research Project in Biochemistry 
BCH448H Structure and Function of the Nucleus 

Awards and Distinctions

2023-2024 — Jean D'Alembert Chair, Université Paris-Saclay  
2020 — Mid-Career Excellence in Graduate Teaching and Mentorship, University of Toronto  
2014 — Ontario Early Researcher Award  
2013 — Canadian Institute for Health Research New Investigator Award  
2011 — Connaught New Researcher Award  
2004-2007 — Jane Coffin Childs Memorial Research Fund Postdoctoral Fellow