Abstract
Large numbers of gross chromosomal rearrangements (GCRs) are frequently observed in many cancers. High mobility group 1 (HMG1) protein is a non-histone DNA-binding protein and is highly expressed in different types of tumors. The high expression of HMG1 could alter DNA structure resulting in GCRs. Spt2p is a non-histone DNA binding protein in Saccharomyces cerevisiae and shares homology with mammalian HMG1 protein. We found that Spt2p overexpression enhances GCRs dependent on proteins for transcription elongation and polyadenylation. Excess Spt2p increases the number of cells in S phase and the amount of single-stranded DNA (ssDNA) that might be susceptible to cause DNA damage and GCR. Consistently, RNase H expression, which reduces levels of ssDNA, decreased GCRs in cells expressing high level of Spt2p. Lastly, high transcription in the chromosome V, the location at which GCR is monitored, also enhanced GCR formation. We propose a new pathway for GCR where DNA intermediates formed during transcription can lead to genomic instability.
Highlights
Maintaining genomic stability is crucial for cell survival and normal cell growth
We tested whether high expression of its yeast homologue, Spt2p, could induce pathogenic effect including gross chromosomal rearrangements (GCRs) formation
Further studies to find mechanisms resided in GCR formation by Spt2p revealed that excess Spt2p increased single-stranded DNA to produce GCR
Summary
Maintaining genomic stability is crucial for cell survival and normal cell growth. Different genetic disorders, including cancers, display different forms of genomic instabilities. There is growing evidence supporting the hypothesis that gross chromosomal rearrangements (GCRs) found in different cancers are caused by the pre-acquisition of mutator mutations [1,2,3,4]. Identification of such mutator mutations could help to identify more genes participating in carcinogenesis. There are multiple pathways for the suppression of genomic instability The importance of these pathways in human cancer development has been uncovered by observations of mutations in their human homologous genes in many cancers or cells from cancer pre-disposed syndrome patients [1,2,4,9]
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