Belasco Lab - Microbiology

Joel G. Belasco
Professor; Coord Structural Biology Program
Department of Microbiology (Skirball) and Structural Biology

540 First Avenue Floor 3 Room Labs 2 & 3
Skirball Institute
New York, NY 10016
Phone: 212-263-5409
Fax: 212-263-8951
Email: Joel.Belasco@med.nyu.edu

 

KEY INTERESTS:

mRNA degradation, mRNA stability, mRNA decay, RppH, RNA pyrophosphohydrolase, Nudix, monophosphate, triphosphate, ribonuclease, endonuclease, exonuclease, RNase E, RNase J, bacteria, E. coli, B. subtilis, 5’ end, microRNA, miRNA, RISC, Argonaute, GW182, deadenylation, poly(A), translation, gene expression, gene regulation

BIOGRAPHIC DETAILS:

Graduate Education:

Harvard University, Ph.D., 1980 (Chemistry)

Postdoctoral Training:

Harvard University, 1980-1981 (Chemistry)
Stanford University, 1981-1985 (Genetics)

Academic Appointments

1985-1991 Assistant Professor of Microbiology and Molecular Genetics, Harvard Medical School
1991-1996 Associate Professor of Microbiology and Molecular Genetics, Harvard Medical School
1996- Professor of Microbiology, New York University School of Medicine

Major Responsibilities:

1998-2008 Coordinator, Structural Biology Program, Skirball Institute, NYU School of Medicine
2007- Graduate advisor, Microbiology Training Program, NYU School of Medicine

Major Honors:

1986-1988 Charles A. King Trust Research Fellowship
1993-1997 American Cancer Society Faculty Research Award

RESEARCH INTERESTS:

Post-transcriptional Gene Regulation

Post-transcriptional processes play a crucial role in controlling gene expression in all organisms. Our research is aimed at elucidating the molecular mechanisms by which such control is imposed. We are particularly interested in two important means by which genes are regulated post-transcriptionally: messenger RNA degradation and repression by microRNAs and siRNAs. The goal of our investigations is to identify and characterize the proteins, RNA elements, and molecular mechanisms that govern these key regulatory processes in bacterial and mammalian cells.

 

 

mRNA degradation

In bacteria, the lifetimes of mRNAs can differ by more than an order of magnitude, with profound consequences for gene expression. For many years it had been assumed that bacterial mRNA degradation begins with endonucleolytic cleavage at internal sites. However, our recent findings have challenged that view by showing that mRNA decay can instead be triggered by a prior non-nucleolytic event that marks transcripts for rapid turnover: the rate-determining conversion of the 5' terminus from a triphosphate to a monophosphate. In Escherichia coli, this modification creates better substrates for the endonuclease RNase E, whose cleavage activity is greatly enhanced when the RNA 5' end is monophosphorylated, whereas in Bacillus subtilis it triggers 5'-exonucleolytic degradation by RNase J. We have identified the pyrophosphate-removing hydrolase responsible for that 5'-terminal event, the first such bacterial enzyme ever characterized. The inability of this RNA pyrophosphohydrolase to modify 5' ends that are structurally sequestered by a stem-loop helps to explain the stabilizing influence of 5'-terminal base pairing on mRNA lifetimes in vivo. Interestingly, this master regulator of 5'-end-dependent mRNA degradation in bacteria not only catalyzes a process functionally reminiscent of eukaryotic mRNA decapping but also bears an evolutionary relationship to the eukaryotic decapping enzyme Dcp2.

MicroRNA function

Human cells contain hundreds of different microRNAs, short RNA molecules that function as negative genetic regulators. In animal cells, microRNAs act by annealing to mRNAs to which they are partially complementary. Our studies have shown that microRNAs inhibit gene expression not only by repressing translation but also by directing rapid poly(A) tail removal, thereby hastening mRNA degradation. Analogously, small interfering RNAs (siRNAs), the mediators of RNA interference, inhibit the function of fully complementary mRNAs both by guiding endonucleolytic cleavage of those messages and by repressing their translation.

We have further shown that, in human cells, CCR4-NOT is the deadenylase whose action is stimulated by the multiprotein complex (RISC) that accompanies microRNAs to their mRNA targets. Interestingly, that complex appears to facilitate deadenylation not by recruiting CCR4-NOT to mRNA but rather by making the autonomous encounters of the deadenylase with poly(A) more productive. The ability of microRNAs to expedite deadenylation does not result from decreased translation; nor does translational repression by microRNAs require a poly(A) tail. These findings indicate that microRNAs utilize two distinct post-transcriptional mechanisms to downregulate gene expression.

SELECTED PUBLICATIONS:

Bacterial RNA degradation

An RNA pyrophosphohydrolase triggers 5’-exonucleolytic degradation of mRNA in Bacillus subtilis
Richards J, Liu Q, Pellegrini O, Celesnik H, Yao S, Bechhofer DH, Condon C, Belasco JG
Journal: Mol. Cell Sept 16;43(6):940-9 (2011)
PMID: 21925382

All Things Must Pass: Contrasts and Commonalities in Eukaryotic and Bacterial mRNA decay
Belasco J G
Journal: Nat. Rev. Mol. Cell Biol. 11: 467-478 (2010)
PMID: 20520623

RNase E autoregulates its Synthesis in Escherichia coli by Binding Directly to a Stem-loop in the rne 5’ untranslated Region
Schuck A, Diwa A, Belasco J G
Journal: Mol. Microbiol. 72: 470–478 (2009)
PMID: 19320830

The bacterial enzyme RppH triggers messenger RNA degradation by 5’ pyrophosphate removal
Deana A, Celesnik H, Belasco J G
Journal: Nature 451: 355-358 (2008)
PMID: 18202662

Initiation of RNA Decay in Escherichia coli by 5’ pyrophosphate removal
Celesnik H, Deana A, Belasco J G
Journal: Mol. Cell 27: 79-90 (2007)
PMID: 17612492

Regulation by microRNAs

CCR4-NOT Deadenylates mRNA associated with RNA-induced silencing complexes in human cells
Piao X, Zhang X, Wu L, Belasco J G
Journal: Mol. Cell. Biol. 30: 1486-1494 (2010)
PMID: 20065043

Importance of Translation and Nonnucleolytic Ago Proteins for On-target RNA Interference
Wu L, Fan J, Belasco J G
Journal: Curr. Biol. 18: 1327-1332 (2008)
PMID: 18771919

MicroRNAs Direct Rapid Deadenylation of mRNA
Wu L, Fan J, Belasco J G
Journal: Proc. Natl. Acad. Sci. USA 103: 4034-4039 (2006)
PMID: 16495412

Micro-RNA Regulation of the Mammalian lin-28 Gene During Neuronal Differentiation of Embryonal Crcinoma Cells
Wu L, Belasco J G
Journal: Mol. Cell. Biol. 25: 9198-9208 (2005)
PMID: 16227573

 

LAB MEMBERS:

NAME

POSITION

TELEPHONE

EMAIL

Joel Belasco, Ph.D.

Principal Investigator

212-263-5409

joel.belasco@med.nyu.edu

Tricia Foley, Ph.D.

Postdoctoral Fellow

212-263-5404

patricia.foley@med.nyu.edu

Ping-kun Hsieh

Graduate Student

212-263-5404

ping-kun.hsieh@med.nyu.edu

Monica Hui, Ph.D.

Postdoctoral Fellow

212-263-5404

monica.hui@med.nyu.edu

Kristin Kotulak, Ph.D.

Postdoctoral Fellow

212-263-5404

kristin.felice@med.nyu.edu

Dan Luciano

Graduate Student

212-263-5404

dan.luciano@med.nyu.edu

Jamie Richards, Ph.D.

Postdoctoral Fellow

212-263-5404

jamie.richards@med.nyu.edu

 

PROFESSIONAL LINKS:

Skirball Institute of Biomolecular Medicine