Arvsmassan hos alla levande organismer består av DNA. Arvsmassan nedärvs från en generation till nästa, via en process vi kallar för DNA replikation. Men arvsmassan är i sig själv tyst och de nedärvda generna måste uttryckas innan de egenskaper som finns nedärvda i arvsmassan kan komma till nytta. Detta sker genom att informationen i arvsmassan översätts till en RNA molekyl, via en process vi kallar för RNA transkription, dvs. en RNA kopia av DNA mo-lekylens information skapas. Den RNA molekylen kallas för budbärar RNA (mRNA) och den fungerar precis som namnet antyder som en budbärare med information som används vid tillverkningen av de för cellen viktiga protei-nerna. Processen som syntetiserar protein kallas för translation. Det behövs ett stort antal komplexa maskinerier för att hela den här processen skall fungera.
Det behövs åtminstone ett DNA syntesmaskineri, ett RNA syntesmaskineri och ett protein syntesmaskineri. I mitt avhandlingsarbete har jag studerat en komponent som påverkar RNA syntesmaskineriet. Komponenten heter poly(A)-specifikt ribonukleas och kallas för PARN. PARN är ett enzym som bryter ned s.k. poly(A) svansar som finns på RNA molekyler. PARN upptäck-tes för drygt 25 år sedan. Sedan dess har den gängse uppfattningen varit att PARN bryter ner RNA molekyler så att de försvinner. För knappt 10 år sedan upptäcktes det att nedbrytning medierad av PARN även ledde till att RNA molekyler mognade till. Det var överraskande! Mitt avhandlingsarbete har lett till ytterligare en överraskning, då vi har kunnat visa att PARN även har en annan viktig roll att fylla – PARN ser till att våra kromosomer som består av DNA inte bryts ned! Hur kunde vi komma fram till en sådan överraskande upptäckt?
Vi studerade i samarbete med en forskargrupp i Kanada en patient som led av en allvarlig utvecklingsstörning som orsakades av att genen som kodade för enzymet PARN var muterad. En konsekvens av den genetiska skadan i genen för PARN var att patientens kromosomer blev instabila, de trasades sönder i sina ändar. Ändarna på kromosomerna kallas för telomerer. Det finns ett en-zym som kallas för telomeras som behövs vid syntesen av kromosomernas telomerändar. Det enzymet är mycket speciellt då det behöver en liten RNA molekyl till sin hjälp för att fungera. Det visade sig att just den RNA moleky-len var beroende av enzymet PARN för att bildas. Detta innebar att patienten som saknande enzymet PARN även saknade ett aktivt telomeras, vilket i sin tur ledde till att kromosomernas ändar trasades sönder och blev kortare och
kortare med tiden. När kromosomerna blir alltför korta leder det till att just den cellen med för korta telomerer dör. Detta visade sig vara en av huvudor-sakerna till att den patient vi studerade blev allvarligt sjuk.
Efter det att vi gjort den upptäckten genomförde vi två följdstudier. I den ena tittade vi i detalj på vilka gener som fungerade som förväntat eller inte i celler från den första patienten vi identifierat. Vi inkluderade i den studien även material från andra patienter med allvarliga fel i genen för PARN. På så sätt har vi nu skaffat oss en översiktsbild på konsekvenser som fel i enzymet för PARN har för en cell. Den här typen av kunskap är viktig för att i detalj kunna förstå PARNs fysiologiska roll i en cell. Vi har nu fått många nya ingångs-vinklar som behövs för att förstå vilken roll PARN har i en cell. Inte helt ovän-tat har det visat sig att det inte enbart är syntesen av kromosomernas ändar som är beroende av PARN. Många andra livsviktiga processer är beroende av att PARN fungerar som det ska.
I den andra följdstudien bestämde vi oss för att etablera en experimentell djur-modell där vi med hjälp av gensaxen CRISPR/Cas9 förstört genen för PARN.
Vi valde zebrafiskar som vår djurmodell. Orsaken till det var att zebrafiskar är som människan ett ryggradsdjur, att de är lätta att föröka och att det finns en stor kunskap om hur zebrafiskar utvecklas, hela vägen från ett befruktat ägg till en vuxen fisk. Det har varit ett tidsödande projekt att genomföra men vi har nu lyckats med föresatsen att etablera ett zebrafisk modellsystem i vilket vi kan studera PARNs fysiologiska roll under en hel livscykel hos zebrafisken.
Till vår stora belåtenhet utvecklar zebrafiskarna, som vi erhållit, många sjuk-domssymptom som överlappar med de sjuksjuk-domssymptom som patienter med en skadad PARN gen får, inklusive en ökad förekomst av trasiga kromosom-ändar. Vi är därför övertygade att våra fortsatta studier av vårt zebrafisk mo-dellsystem kommer att få stor betydelse för vår förståelse av PARNs funkt-ionella roll och hur allvarliga sjukdomsbilder kan uppstå på grund av fel i ge-nen för PARN.
50
Acknowledgements
I would like to express my deep gratitude to many people who inspired, en-couraged, motivated and helped me all through this PhD journey.
First of many, my supervisor Anders Virtanen, thanks for believing in me to handle such complicated projects during the time in your lab. I have learnt so many things from you both professional and personal. I would cherish the fun moments that we spent especially the discussions on the day offs during the conferences. Many thanks for being a great mentor and helped me in many ways through this journey.
My co-supervisor Staffan Svärd for the support in the department.
I would like to thank the funding sources, UU Bioimics for funding my PhD studies, AML/Smålands nation and Sederholms/Uppsala university for conference travel grants and MEDGENET travel grant for EMBL workshop.
I thank NGI/Uppsala and UPPMAX for providing the computational re-sources.
I would like to thank
Micke for your support, discussions and inputs in the thesis.
Andrew for your support and help on linguistic revision of the thesis.
Kristine for your logical inputs and linguistic revision of the thesis.
Former and current members of poly(A) lab group Per, Niklas, Lei, Mattias, Caroline and project students Andreas, Sangeetha, Varshni, Jens, Ger-gana, Spandana, Afsaneh and Malick for your support
Phani for your help and support in RNA seq analysis, and other colleagues in the lab corridor Malavika, Fredrik, Abishek, Ram and Mao for the support.
All Micros especially to Gerhart, Fredrik and Erik for your suggestions and inputs.
Administration staff and other people who aided me at the department.
Special thanks to the collaborators especially Johan, Beata and Tiffany at EBC zebrafish facility, Axen and Hampus at SVA, Uppsala, Santosh and Yigal in Toronto, Lois and Alison in Texas.
I would like to extend my gratitude to
Many friends in India who have been supportive to me and my family, espe-cially, Venkat, Anil, Ramana, Ramesh, Tammi, BT and Swapna.
Friends in Uppsala who have made this journey memorable with lots of fun especially Charan, Chandu anna-Geeta vadina, Sudarsan-Kristine, Hari-Sharanya, Srinu-Sony, Varun-Prathyusha, Manoj-Kanaka, Sasi anna-Archana, Gopi-Sandhya, Venu, Ravi anna-Sushma vadina, Suneel, Lax-mikanth, Ramam, Vivek anna-Lakshmi garu, Prakash anna-Ammulu, Raghuveer-Madhuri, Kiran anna-Bhavya, Phani-Sirisha, Naresh-Sound-arya, Mahesh and Sarita and other friends in Indian/Telugu community.
I would like to thank my extended family Uma-Chandrakanth and my in-law parents Venkat Ramulu-Prameela for their constant support and love through all these years. My sister & brother-in-law Bhulaksmi-Narayana, without you, I could not even come to Sweden to pursue higher studies, thanks a ton for your encouragement, moral support and guidance. Thanks to Pooji and Gokul for all the fun and support.
Finally, I would like to mention my family members, without their support and encouragement I wouldn’t have come this far to fulfill my dreams. My loving parents Venkateswarlu-Mahalakshmi, thanks for all sacrifices you have made to comfort my life, the least I can do in return is to dedicate this thesis. My kid Keshvin, thanks for being such a nice and understanding kid.
You became my little boss at home pushing me to work. My wife Manu, you have been a best friend and shared every fun and frustration that I have gone through this journey. As a soul mate, I really feel that thanking you is like thanking myself, but still a big thanks! for the love, support and being my strength.
52
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