Retrotranspozoni kao regulatori ekspresije gena

undergraduate thesis

• Title (english): Retrotransposons as gene expression regulators
• Author: Hana Rimanić
• Mentor: Ivana Ivančić Baće (mentor)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2017, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology

Abstract

Retrotranspozoni su pokretni genetički elementi koji se kreću po genomu putem RNA intermedijera. Tri su glavne grupe retrotranspozona; LTR (long terminal repeat) retrotranspozoni, elementi LINE (long interspersed elements) i elementi SINE (short interspersed elements). U ovom radu fokusirali smo se na elemente LINE i SINE koji vrše transpoziciju putem „copy and paste“ mehanizma. Prvi „copy“ korak uključuje transkripciju s RNA polimerazom II nakon čega slijedi translacija. U „paste“ koraku enzim endonukleaza radi ureze u ciljnoj DNA te reverzna transkriptaza prepisuje RNA intermedijer u DNA. Kažemo da su elementi LINE autonomni zato što kodiraju za sve proteine potrebne za svoju retrotranspoziciju, dok su elementi SINE neautonomni i enzime „posuđuju“ od LINE. Iako većina transpozicija uzrokuje neutralne ili deletirajuće mutacije, ovi retrotranspozoni imaju mnogo različitih utjecaja na ekspresiju gena. Dosad provedena istraživanja otkrila su velik broj uloga koje ovi elementi imaju u stanicama domaćina; djeluju kao utišivači ili pojačivači transkripcije, mogu stvoriti nova mjesta izrezivanja koja rezultiraju s alternativno izrezanim eksonima s intronskim sekvencama. Također je nađeno da u stresnim uvjetima mogu inhibirati velik dio stanične translacije vežući se dsRNA-ovisnu protein kinazu. Uređivanjem A do I zbog deaminacije adenina do inozina dolazi do promjene kodona a time i ugradnje alternativne aminokiseline prilikom translacije na ribosomu. Promjena baza također uzrokuje kriva sparivanja u dvolančanoj RNA i narušava joj strukturu i samim time tip proteina koji će se na nju vezati. S obzirom da je insercija retrotranspozona nužno mutagena i može dovesti do raznih poremećaja, organizmi su razvili brojne mehanizme da bi zaštitili svoje genome. Utišavanje transkripcije metilacijom DNA i histona, razne molekule RNA koje se specifično vežu na LINE i SINE transkripte i degradiraju ih, specifične grupe proteina koje vrše restrikciju retrotranspozicije i autofagija neki su od načina obrane od insercije retrotraspozonske DNA. Zadnjih godina se otkrilo mnogo o tome kako sve retrotranspozoni utječu na ekspresiju gena i o njihovoj povezanosti s čak oko stotinjak genski nasljednih bolesti. Otkriće da je retrotranspozicija aktivna u somatskim stanicama tokom cijelog života daje naslutiti da bi se daljnjim istraživanjima mogli otkriti dosad nepotpuno razjašnjeni mehanizmi nastanka nenasljednih bolesti i bolesti povezanih sa starenjem.

Abstract (english)

Retrotransposons are transposable elements that transpose via an RNA-intermediate. There are three major retrotransposon orders; long terminal repeat (LTR) retrotransposons, long interspersed elements (LINEs) and short interspersed elements (SINEs). Here we focus on LINEs and SINEs. They transpose via a copy-and-paste mechanism. The copy step involves gene transcription by RNA polymerase II followed by translation. In the paste step enzyme endonuclease nicks the target DNA and reverse-transcriptase transcribes the RNA intermediate into the DNA. LINEs are autonomous because they encode for all the proteins necessary for retrotransposition whereas SINEs don't, so they use enzymes from LINEs. These retrotransposons have many influences on gene expression besides causing neutral mutations or deletions in the genome. The so far conducted studies demonstrate that LINEs and SINEs perform many different roles within cells. They can regulate gene expression by acting as transcription enhancers or silencers. They can create new splicing sites resulting in alternatively spliced exons. It is also found that in stressful conditions they can inhibit a majority of the cellular translation by binding and thus activating dsRNA-dependent protein kinase. Adenosine-to-Inosine posttranscriptional editing, where adenosine is deaminated to inosine can lead to amino-acid recoding and can also disrupt the structure of dsRNA by creating mismatches. Considering that retrotransposition is necessarily mutagenic and has the potential to cause disease, organisms have developed multiple mechanisms to protect their genomes; transcriptional silencing by DNA and histone methylation, sequence specific RNA degradation to eliminate LINE and SINE transcripts, specific groups of proteins that restrict retrotransposition and degradation by autophagy. Although we now know a lot about how retrotranposons impact gene expression and have identified around 100 genetic diseases that are linked to retrotransposition. While retrotransposition in germline cells is hereditary, there is still a lot to be discovered about how and why retrotansposition occurs in somatic cells and can cause disease. These discoveries could lead to better understanding of molecular pathogenesis of non-hereditary and age-related illneses.

• Keywords: retrotranspozoni; ekspresija gena
• Keywords (english): retrotransposons; gene expression
• Language: croatian
• URN:NBN: urn:nbn:hr:217:281497
• Study programme: Title: Molecular Biology; Study programme type: university; Study level: undergraduate; Academic / professional title: sveučilišni/a prvostupnik/prvostupnica (baccalaureus/baccalaurea) molekularne biologije (sveučilišni/a prvostupnik/prvostupnica (baccalaureus/baccalaurea) molekularne biologije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2017-09-08 10:05:16