{"id":6378,"date":"2026-10-19T09:48:50","date_gmt":"2026-10-19T09:48:50","guid":{"rendered":"https:\/\/phd.hi.is\/doktorsvorn\/doktorsvorn-i-lif-og-laeknavisindum-karen-kristjansdottir\/"},"modified":"2026-10-19T09:48:50","modified_gmt":"2026-10-19T09:48:50","slug":"doktorsvorn-i-lif-og-laeknavisindum-karen-kristjansdottir","status":"publish","type":"phd_defence","link":"https:\/\/phd.hi.is\/en\/doktorsvorn\/doktorsvorn-i-lif-og-laeknavisindum-karen-kristjansdottir\/","title":{"rendered":"Doktorsv\u00f6rn \u00ed l\u00edf- og l\u00e6knav\u00edsindum – Karen Kristj\u00e1nsd\u00f3ttir"},"content":{"rendered":"
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F\u00f6studaginn 6. desember 2024 ver Karen Kristj\u00e1nsd\u00f3ttir doktorsritger\u00f0 s\u00edna \u00ed l\u00edf- og l\u00e6knav\u00edsindum vi\u00f0 L\u00e6knadeild H\u00e1sk\u00f3la \u00cdslands. Ritger\u00f0in ber heiti\u00f0: \u00c1hrif RNA sviperf\u00f0a \u00e1 tj\u00e1ningu DNA vi\u00f0ger\u00f0argena. Epitranscriptomic regulation of DNA repair genes.<\/strong><\/p>\n

Andm\u00e6lendur eru dr. John Krais, lektor vi\u00f0 Washington University School of Medicine \u00ed St. Louis, og dr. Francesca Aguilo, d\u00f3sent vi\u00f0 Ume\u00e5 University \u00ed Sv\u00ed\u00fej\u00f3\u00f0.<\/p>\n

Umsj\u00f3narkennari og lei\u00f0beinandi var Stef\u00e1n \u00de. Sigur\u00f0sson, pr\u00f3fessor og lei\u00f0beinandi var \u00deorkell Gu\u00f0j\u00f3nsson, d\u00f3sent. Auk \u00feeirra s\u00e1tu \u00ed doktorsnefnd Hans T\u00f3mas Bj\u00f6rnsson, pr\u00f3fessor og Anindya Roy, pr\u00f3fessor.<\/p>\n

S\u00e6d\u00eds S\u00e6varsd\u00f3ttir, pr\u00f3fessor og varadeildarforseti L\u00e6knadeildar, stj\u00f3rnar ath\u00f6fninni sem fer fram \u00ed H\u00e1t\u00ed\u00f0asal H\u00e1sk\u00f3la \u00cdslands og hefst kl. 9.00.<\/p>\n

\u00c1grip<\/strong><\/p>\n

H\u00e6fni frumna til a\u00f0 greina og gera vi\u00f0 DNA-skemmdir er eitt mikilv\u00e6gasta hlutverk e\u00f0lilega starfandi frumna, \u00fear sem DNA-skemmdir eru ein helsta ors\u00f6k erf\u00f0afr\u00e6\u00f0ilegs \u00f3st\u00f6\u00f0ugleika, sem er einkenni flestra krabbameina. DNA-tv\u00ed\u00fe\u00e1tta brot (DTB) eru s\u00e9rstaklega alvarleg tegund DNA-skemmda. Stj\u00f3rnun \u00e1 vi\u00f0ger\u00f0um DNA-DTB er afar mikilv\u00e6g, \u00fear sem gallar \u00ed \u00feessum vi\u00f0ger\u00f0um geta leitt til frumudau\u00f0a og stu\u00f0la\u00f0 a\u00f0 myndun krabbameina. \u00dev\u00ed ver\u00f0ur vi\u00f0ger\u00f0 \u00e1 DNA-DTB a\u00f0 vera n\u00e1kv\u00e6m og vel stj\u00f3rna\u00f0 til a\u00f0 vi\u00f0halda erf\u00f0afr\u00e6\u00f0ilegum st\u00f6\u00f0ugleika og tryggja e\u00f0lilega frumustarfsemi.<\/p>\n

Me\u00f0 \u00feessari ranns\u00f3kn s\u00fdnum vi\u00f0 fram \u00e1 n\u00fdja RNA-sviperf\u00f0astj\u00f3rnun \u00e1 vi\u00f0ger\u00f0um DNA-DTB. Ni\u00f0urst\u00f6\u00f0ur okkar benda til \u00feess a\u00f0 tveir d\u00edox\u00fdgenasar, sem tilheyra AlkB-pr\u00f3tein fj\u00f6lskyldunni, ALKBH3 og FTO (einnig \u00feekktur sem ALKBH9), stj\u00f3rni pr\u00f3teintj\u00e1ningu RNF168, lykilpr\u00f3teins sem tekur \u00fe\u00e1tt \u00ed vi\u00f0ger\u00f0um \u00e1 DTB. RNA-sviperf\u00f0ir v\u00edsa til stj\u00f3rnunar \u00e1 genatj\u00e1ningu eftir umritun me\u00f0 breytingum \u00e1 RNA, sem geta haft \u00e1hrif \u00e1 virkni og uppbyggingu RNA-sameindarinnar \u00e1n \u00feess a\u00f0 valda breytingum \u00e1 r\u00edb\u00f3sakjarns\u00fdrur\u00f6\u00f0inni. RNA-breytingar finnast \u00e1 \u00f6llum ger\u00f0um RNA, \u00fear \u00e1 me\u00f0al mRNA, \u00fear sem met\u00fdleringar eru algengasta form breytinga.<\/p>\n

Ni\u00f0urst\u00f6\u00f0ur \u00feessarar ranns\u00f3knar benda til \u00feess a\u00f0 ALKBH3 og FTO stj\u00f3rni RNF168 me\u00f0 \u00fev\u00ed a\u00f0 fjarl\u00e6gja met\u00fdleringar af RNF168 mRNA. ALKBH3 fjarl\u00e6gir N1-met\u00fdladen\u00f3s\u00edn (m1A), en FTO fjarl\u00e6gir N6-met\u00fdladen\u00f3s\u00edn (m6A). Gena\u00fe\u00f6ggun \u00e1 ALKBH3 og FTO leiddi \u00ed lj\u00f3s a\u00f0 frumur sem skortir ALKBH3 e\u00f0a FTO s\u00fdndu sterk merki um truflun \u00e1 starfsemi RNF168, \u00fear \u00e1 me\u00f0al vanh\u00e6fni 53BP1-pr\u00f3teins til a\u00f0 tengjast DNA-DTB. Frekari ranns\u00f3knir s\u00fdndu fram \u00e1 a\u00f0 frumur me\u00f0 skerta virkni ALKBH3 og FTO h\u00f6f\u00f0u lakari getu til a\u00f0 gera vi\u00f0 DTB. Einnig kom \u00ed lj\u00f3s aukinn erf\u00f0afr\u00e6\u00f0ilegur \u00f3st\u00f6\u00f0ugleiki og auki\u00f0 varnarleysi fyrir lyfjum sem valda DNA skemmdum vi\u00f0 tap \u00e1 ALKBH3 og FTO.<\/p>\n

\u00deessar ni\u00f0urst\u00f6\u00f0ur benda til n\u00fdrrar ger\u00f0ar stj\u00f3rnunar \u00e1 RNF168 og s\u00fdna a\u00f0 mRNA-breytingar hafa \u00e1hrif \u00e1 DNA-DTB vi\u00f0ger\u00f0arsv\u00f6run. Enn fremur gefa ni\u00f0urst\u00f6\u00f0urnar \u00far \u00feessu verkefni v\u00edsbendingu um samspil milli alk\u00fdleringarvi\u00f0ger\u00f0ar og DNA-DTB vi\u00f0ger\u00f0ar. Tap \u00e1 ALKBH3 og FTO g\u00e6ti reynst gagnlegt sem v\u00edsbending fyrir sv\u00f6run vi\u00f0 krabbameinsme\u00f0fer\u00f0, b\u00e6\u00f0i vegna skorts \u00e1 alk\u00fdleringarvi\u00f0ger\u00f0 og hugsanlega vegna galla \u00ed DNA-DTB vi\u00f0ger\u00f0, sem undirstrikar m\u00f6gulegan kl\u00edn\u00edskan \u00e1vinning af \u00feessari ranns\u00f3kn.<\/p>\n

Abstract<\/strong><\/p>\n

One of the most vital functions of a normal, functioning cell is its ability to detect and repair DNA damage, as damaged DNA is a primary cause of genomic instability, a hallmark of most cancers. DNA double-strand breaks (DSBs) are the most severe type of DNA damage. Regulation of DNA DSB repair is critical because unrepaired or incorrectly repaired DSBs can result in cell death or lead to increased genomic instability, raising the risk of cancer development. Therefore, the regulation of DSB repair must be precise and tightly controlled to prevent genomic instability and ensure proper cellular function.<\/p>\n

The research presented in this thesis introduces a novel epitranscriptomic regulatory mechanism of DNA DSB repair. Here, we demonstrate that two dioxygenases from the AlkB alkylation repair protein family, ALKBH3 and FTO (also known as ALKBH9), regulate the protein expression of RNF168, a key protein involved in DSB repair. Epitranscriptomics refers to the regulation of gene expression through RNA modifications, which influence RNA structure and function without altering its sequence. RNA modifications are present on all types of RNA, including mRNA, with methylations being the most common form of mRNA modification.<\/p>\n

In our research, ALKBH3 and FTO were found to regulate RNF168 by removing methylation marks from RNF168 mRNA\u2014ALKBH3 removed N1-methyladenosine (m1A), and FTO removed N6-methyladenosine (m6A). Cells depleted of ALKBH3 or FTO exhibited significant RNF168 dysfunction, including impaired 53BP1 recruitment to DNA DSBs and altered DNA DSB repair dynamics. Subsequent studies revealed heightened genomic instability and increased sensitivity to genotoxic agents in cells lacking either ALKBH3 or FTO.<\/p>\n

The findings from this project establish a novel epitranscriptomic regulatory mechanism for RNF168, linking mRNA modifications to DNA DSB repair signaling. Additionally, our results highlight an interplay between alkylation repair and DNA repair, with potential implications for cancer biology. Loss of ALKBH3 and FTO contributes to DDR defects and may serve as biomarkers for cancer prognosis and treatment response. These discoveries enhance our understanding of how RNA modifications impact genomic maintenance and underscore their clinical relevance in cancer and DNA repair research.<\/p>\n

Um doktorsefni\u00f0<\/strong><\/p>\n

Karen Kristj\u00e1nsd\u00f3ttir er f\u00e6dd \u00e1ri\u00f0 1989 \u00e1 Selfossi. H\u00fan lauk BS-pr\u00f3fi \u00ed l\u00edfefnafr\u00e6\u00f0i fr\u00e1 H\u00e1sk\u00f3la \u00cdslands 2012 og MS-gr\u00e1\u00f0u \u00ed sameindal\u00edffr\u00e6\u00f0i fr\u00e1 Syddansk Universitet \u00e1ri\u00f0 2016. Karen h\u00f3f doktorsn\u00e1m vi\u00f0 L\u00e6knadeild H\u00cd 2019. Ranns\u00f3knarverkefni\u00f0 hlaut styrk \u00far Ranns\u00f3knarsj\u00f3\u00f0i Rann\u00eds og hlaut Karen einnig styrk fr\u00e1 Bl\u00e1a naglanum. Samhli\u00f0a doktorsn\u00e1mi hefur Karen sinnt a\u00f0sto\u00f0arkennslu vi\u00f0 H\u00e1sk\u00f3la \u00cdslands, seti\u00f0 \u00ed stj\u00f3rn L\u00edfv\u00edsindaseturs sem fulltr\u00fai doktorsnema fr\u00e1 2020 til 2022 \u00e1samt \u00fev\u00ed a\u00f0 sitja \u00ed stj\u00f3rn SK\u00cd (Samt\u00f6k um krabbameinsranns\u00f3knir \u00e1 \u00cdslandi) fr\u00e1 2022 til 2024. Foreldrar hennar eru S\u00f3lveig Sigmarsd\u00f3ttir og Kristj\u00e1n M\u00e1r Gunnarsson. Karen er gift Zenel Demiri l\u00e6kni og saman eiga \u00feau einn son, Ara Demiri.<\/p>\n

\u00a0<\/p>\n

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