The tRNA Splicing Endonuclease Modulates Cell Division

Researchers studying cell replication at the molecular level have learned that the human tRNA splicing endonuclease enzyme complex has functions related to both pre-tRNA splicing and to pre-mRNA 3' (3-prime) end formation, indicating a central role in controlling the process of cell division.

tRNA splicing removes introns, the nucleotide sequences in eukaryotes that must be excised from a structural gene transcript in order to convert the transcript into a mature messenger RNA molecule containing only coding sequences that can be translated into the amino acid sequence of a polypeptide. The splicing is catalyzed by tRNA splicing endonuclease. Failure of this enzyme to function results in rapid and uncontrolled cell division leading to diseases such as leukemia, lymphoma, multiple myeloma, solid tumors, and inflammatory diseases such as psoriasis.

Investigators at the drug discovery company PTC Therapeutics, Inc. (South Plainfield, NJ, USA) have identified and characterized the human tRNA splicing endonuclease enzyme complex. They reported in the April 30, 2004, issue of Cell that the enzyme consists of HsSen2, HsSen34, HsSen15, and HsSen54, which are homologues of tRNA endonuclease subunits previously found in yeast. When siRNA was used to deplete SEN2, defects were found in maturation of both pre-tRNA and pre-mRNA.

Senior author Dr. Christopher R. Trotta, a senior scientist at PTC Therapeutics, said, "Overexpression of tRNA and mRNA is a key factor in the deregulation of translation that allows cancer cells to grow uncontrollably. This newly discovered biochemical pathway represents an Achilles' heel of tumor cell growth and opens a new door in the development of therapeutics.”




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