Primate-specific stress-induced transcription factor POU2F1Z protects human neuronal cells from stress

Abstract

The emergence of new primate-specific genes is an essential factor in human and primate brain development and functioning. POU2F1/Oct-1 is a transcription regulator in higher eukaryotes which is involved in the regulation of development, differentiation, stress response, and other processes. We have demonstrated that the Tigger2 transposon insertion into the POU2F1 gene which occurred in the primate lineage led to the formation of an additional exon (designated the Z-exon). Z-exon-containing primate-specific Oct-1Z transcript includes a short upstream ORF (uORF) located at its 5’-end and the main ORF encoding the Oct-1Z protein isoform (Pou2F1 isoform 3, P14859-3), which differs from other Oct-1 isoforms by its N-terminal peptide. The Oct-1Z-encoding transcript is expressed mainly in human brain cortex. Under normal conditions, the translation of the ORF coding for the Oct-1Z isoform is repressed by uORF. Under various stress conditions, uORF enables a strong increase in the translation of the Oct-1Z-encoding ORF. Increased Oct-1Z expression levels in differentiating human neuroblasts activate genes controlling stress response, neural cell differentiation, brain formation, and organogenesis. We have shown that the Oct-1Z isoform of the POU2F1/Oct-1 transcription factor is an example of a primate-specific genomic element contributing to brain development and cellular stress defense.

The Emergence of a New Isoform of POU2F1 in Primates through the Use of Egoistic Mobile Genetic Elements

“…We have discovered a new POU2F1Z isoform whose translation increases many times under cellular stress. One of the functions of this isoform is to protect cells from the damaging effects of various types of stress [ 10 ]. POU2F1Z mRNA is expressed in all human tissues and cells, but it is found at the maximum level in the cerebral cortex and in lymphoid cells.…”

“…Under normal conditions, the synthesis of this short peptide (uORF) inhibits the translation of the long reading frame (POU2F1Z protein); however, under cellular stress, the synthesis of the short peptide is suppressed and the translation of the POU2F1Z protein is activated [ 10 ].…”

“…We have previously shown that activation of POU2F1Z translation starts under the action of damaging agents and protects cells from cell death [ 10 ]. We assume that this defense mechanism can significantly increase the resistance of cancer cells to chemotherapeutic drugs and non-drug methods of treating malignant tumors.…”