Occurrence and functional implications of somatic retroposition from processed transcripts in rectal tumors

• Grant number: 13/08026-9
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): July 01, 2013
• Effective date (End): June 30, 2015
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Anamaria Aranha Camargo
• Grantee: Ana Paula de Souza Urlass
• Host Institution: Hospital Sírio-Libanês. Sociedade Beneficente de Senhoras (SBSHSL). São Paulo , SP, Brazil

Abstract

Retrotransposons are genetic elements capable to replicate autonomously and to move from one position to another in the genome through an RNA intermediate molecule. non-LTR retrotransposon are abundant in the human genome and among this class of retrotransposons the LINES (Long Interspersed Nuclear Elements) correspond to 21% of the human genome and promote their own retroposition, as well as the retroposition of other non-LTR elements (SINES and VAS) and of processed mRNA molecules, generating retrocopies. Retroposition events mediated by LINE can occur randomly throughout the genome and the insertion of retrocopied sequences can substantially alter genome organization and gene expression pattern. The expression and activity of non-LTR retrotransposons in normal somatic cells are thus repressed by epigenetic and post-transcriptional mechanisms. In tumors, however, somatic retroposition events are favored by global genome hypomethylation and by the presence of mutations in DNA repair genes. The involvement of these events in tumorigenesis is not clear yet, but recent studies suggest that somatic retroposition events involving LINES are frequent in tumors and may contribute functionally to tumor formation and progression, by promoting changes in gene expression and favoring recombination events and chromosomal instability. Somatic retroposition events involving processed transcripts have recently been reported in the literature but were superficially characterized. Given the increased activity of L1 elements in tumors it is likely that these events occur frequently and have important roles in tumorigenesis. In this context, we propose to analyze the occurrence of somatic retroposition events involving processed transcripts in rectal tumors and to explore the functional implications of these events in relation to tumorigenesis, evaluating their possible interference on the transcriptional activity of host genes as well as the formation of chimeric transcripts. We also intend to evaluate the occurrence of these events in relation to certain features present in the tumor genome and known to favor retroposition events such as genome hypomethylation and the presence of mutations in DNA repair genes. Overall this project aims to contribute to a better characterization of retroposition events in human tumors. (AU)