Neoplasia-associated Chromosome Translocations Resulting in Gene Truncation

Abstract

Chromosomal translocations in cancer as well as benign neoplasias typically lead to the formation of fusion genes. Such genes may encode chimeric proteins when two protein-coding regions fuse in-frame, or they may result in deregulation of genes via promoter swapping or translocation of the gene into the vicinity of a highly active regulatory element. A less studied consequence of chromosomal translocations is the fusion of two breakpoint genes resulting in an out-of-frame chimera. The breaks then occur in one or both protein-coding regions forming a stop codon in the chimeric transcript shortly after the fusion point. Though the latter genetic events and mechanisms at first awoke little research interest, careful investigations have established them as neither rare nor inconsequential. In the present work, we review and discuss the truncation of genes in neoplastic cells resulting from chromosomal rearrangements, especially from seemingly balanced translocations.

Keywords: Chromosome aberration; gene truncation; out-of-frame fusion transcript; review; translocation.

Figure 1. The high mobility group AT-hook 2 (HMGA2) gene. The chromosome band location (top) and exon 5 of the gene (bottom) are shown. On exon 5, the Let7 positions are underlined. Additional microRNA target sites predicted by TargetScanHuman 7.2 are also shown. The colors indicate different classes of target sites: Purple is for 8mer, red for 7mer-m8 and blue for 7mer-A1.

Figure 2. The colony stimulating factor 1 (CSF1) gene. Chromosome band location (top), the four transcript variants (middle), and the last nontranslated exon 9 of the variants with accession number NM_172211.4 and NM_000757.6 (bottom) are shown. On exon 9, the G-quadruplex, the AU-rich (ARE) element, and microRNA target sites predicted by TargetScanHuman 7.2 are also shown. The colors indicate different classes of target sites: Purple is for 8mer, red for 7mer-m8 and blue for 7mer-A1.

Figure 3. The Fos proto-oncogene, AP-1 transcription factor subunit (FOS) gene. On the translated part of exon 4, the C-terminal region involved in FOS degradation is shown. In the untranslated part of the exon, the AU-rich (ARE) element and microRNA target sites predicted by TargetScanHuman 7.2 are shown. The colors indicate different classes of target sites: Purple is for 8mer, red for 7mer-m8 and blue for 7mer-A1. In all FOS chimeras, the FOS degradation and the untranslated region are not present.

Figure 4. The mitogen-activated protein kinase 8 (MAP3K8) gene. The chromosome band location (top) and exon 9 of the gene are shown (bottom). On the translated part of exon 9, the C-terminal region the kinase repression domain is shown. The underlined sequence is part of the PEST domain of MAP3K8 protein. The bold sequence is the degradation signal (degron).