We study the biosynthesis of transfer RNA (tRNA), which serves as the adaptor in transferring of the genetic information from mRNA to protein in the cell. Specifically, we investigate transcription of human tRNA genes by RNA polymerase III (Pol III) and subsequent processing and splicing of newly transcribed precursor tRNAs.
Processing of precursor tRNA requires ribonuclease P (RNase P), an essential ribonucleoprotein enzyme. Biochemical purification analyses of nuclear RNase P from human cells have revealed that this large ribonucleoprotein complex has an RNA subunit, termed H1 RNA, and ten distinct protein subunits. We have characterized many of these protein subunits and reconstituted the endonucleolytic activity of RNase P in processing of precursor tRNA in vitro by the use of H1 RNA and recombinant protein subunits. The roles of H1 RNA and its protein subunits in RNA-based catalysis and substrate recognition are being further investigated.
More recent discoveries from our laboratory reveal that a form of human RNase P is required for transcription of small noncoding RNA genes by Pol III. Pol III transcribes an expanding number of genes, including tRNA, 5S rRNA, SRP RNA, 7SK RNA and U6 snRNA genes. The noncoding RNA transcripts of these genes participate in fundamental biological processes, such as transcription, mRNA splicing and translation. RNase P associates with Pol III in initiation complexes, which are controlled by proto-oncogenes and tumor suppressor genes, and binds to chromatin of tRNA and 5S rRNA genes in a cell cycle-dependent manner. Ongoing research focuses on the elucidation of the molecular mechanisms by which RNase P exerts its role on Pol III transcription and how transcription and processing of precursor tRNA are coordinated in confined nuclear compartments.
An emerging area of research concerns the molecular designing and use of RNase P for the inactivation of expression of human genes associated with aging and cancer. This research led to the discovery that RNase P and Pol III respond to cessation of replication progression and DNA damage that lead to mitotic catastrophe and cell death of cancer cells. Moreover, through collaborative work, we have shown that a form of human RNase P is involved in DNA repair of double stranded breaks (DSBs) via the homology directed repair pathway.
- Biochemical studies of catalytic ribonucleoprotein complexes of human RNase P
- Elucidation of the molecular mechanisms by which ribonucleoprotein complexes of RNase P controls gene transcription by RNA polymerase I and III
- RNase P, DNA damage, aging and cancer
An unexpected error has occurred.
An unexpected error has occurred.
Orlovetskie N., Serruya R., Abboud-Jarrous G., and N. Jarrous. 2017. Targeted inhibition of WRN helicase, replication stress and cancer. BBA Reviews on Cancer. 1867, 42-48.
Abu-Zhayia E.R., Khoury-Haddad H., Guttmann-Raviv N., Serruya R., Jarrous N., and N. Ayoub. 2017. A role of human RNase P subunits, Rpp29 and Rpp21, in homology directed-repair of double-strand breaks. Scientific Reports, Sci. Rep. 7, 1002.
Hitrik A., Abboud G., Orlovetskie N., Serruya R. and N. Jarrous. 2016. Targeted inhibition of WRN helicase by external guide sequence and RNase P RNA. BBA-Gene Regulatory Mechanisms 1859, 572-580.
Serruya R., Orlovetskie N., Reiner R., Dehtiar-Zilber Y., Wesolowski D., Altman S., and N. Jarrous. 2015. Human RNase P ribonucleoprotein is required for formation of initiation complexes of RNA polymerase III. Nucleic Acids Res. 43, 5442-5450.
Reiner R., Alfiya-Mor N., Berrebi-Demma M., Wesolowski D., Altman S., and N. Jarrous. 2011. RNA binding properties of conserved protein subunits of human RNase P. Nucleic Acids Res. 39, 5704-5714.
Jarrous N. and V. Gopalan. 2010. Archaeal/eukaryal RNase P: subunits, functions and RNA diversification. Nucleic Acids Res. 38, 7885-7894.
Jarrous, N., Reiner, R., and Y. Dehtiar. 2009. Human RNase P and transcription. In Ribonuclease P. Liu F. and Altman S. Eds. Springer. Protein Rev. 10, 223-234.
Reiner R., Krasnov-Yoeli N., Dehtiar Y., and N. Jarrous. 2008. Function and assembly of a chromatin-associated RNase P that is required for efficient transcription by RNA polymerase I. PLoS One 3, e4072.
Jarrous N. and R. Reiner. 2007. Human RNase P: a tRNA processing enzyme and transcription factor. Nucleic Acids Res. 35, 3519-3524.
Reiner, R., Ben-Asouli, Y., Krilovetzky, I., and N. Jarrous. 2006. A role for the catalytic ribonucleoprotein RNase P in RNA polymerase III transcription. Genes & Dev. 20, 1621-1635.
Mann H., Ben-Asouli Y., Schein A., Moussa S., and N. Jarrous. 2003. Eukaryotic RNase P: role of RNA and protein subunits of a primordial catalytic ribonucleoprotein in RNA-based catalysis. Mol. Cell 12, 925-935.