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DNA-Repair (Nilsen Group)

DNA and RNA quality control in health and disease.

Research focus

DNA repair is the main interest in the group. The term DNA repair covers many different mechanisms that remove damaged or inappropriate bases from DNA. Historically, studies of DNA repair has been motivated by the need for these mechanisms in order to prevent mutations - changes in the genetic code. Studies of DNA repair is therefore important in order to understand how cancer develops and how cancer can be treated. In recent years it has become clear that DNA repair enzymes have many important functions in cells other than to prevent mutations, most importantly in neurobiology to prevent neurodegenerative diseases. We have also recently demonstrated that DNA repair proteins contribute to RNA quality control.

Aims:

  • To study whether DNA damage and mutations may act as a driver of tumorigenesis
  • To study how signal transduction cascades may be elicited by DNA damage to activate cell death pathways in response to chemotherapeutic agents
  • To study how DNA repair mechanisms protect us from premature aging and age-related neurodegenerative diseases
  • To study how DNA repair enzymes maintain telomere length
  • To study how DNA repair proteins contribute to RNA quality Control

Research achievements

  • We have demonstrated that the DNA repair enzyme SMUG1 removes damaged bases from RNA and contribute to RNA quality control (Jobert et al., 2013)
  • We have identified a novel mechanism for induction of autophagy by the chemotherapeutic agent 5-fluorouracil (Erdelyi et al., 2011; SenGupta 2013)
  • We have described transcriptomic and proteomic changes that compensate for the lack of DNA repair in C. elegans and contribute to maintain normal lifespan (Fensgård et al, 2010; Skjeldam et al., 2010; Arczewska et al., 2012; Lans et al 2013)
  • We demonstrated that DNA repair enzymes act to initiate cellular signaling cascades leading to activation of apoptosis (Dengg et al., 2006)
  • We characterized several genome-maintenance enzymes in C. elegans (Skjeldam et al., 2010; Arczewska et al., 2010; Zakaria et al., 2010)

Selected publications

  1. SenGupta, T., Torgersen, M. Kassahun, H., Vellai, T., Simonsen, A., and Nilsen, H. The Base Excision Repair AP-endonucleases functions in the same pathways as Mismatch Repair for Activation of Checkpoint Mediated Autophagy. (2013) Nature Communications 4:267

  2. Lans H, Lindvall JM, Thijssen K, Karambelas AE, Cupac D, Fensgård Ø, Jansen G, Hoeijmakers JHJ, Nilsen H, Vermeulen W. DNA damage leads to progressive replicative decline but extends lifespan of long lived mutant animals. Manuscript accepted for publication (2013) Cell death and differentiation 20(12):1709-18.

  3. Arczewska, KD., Tomazella, GG., Lindvall JM, Kassahun H., Maglioni S., Torgovnick A., Henriksson, J., Matilainen O., Marquis BJ, Nelson, BC., Jaruga, P., Babaie E,Holmberg C., Burglin, TR., Ventura N., Thiede B., Nilsen H. Active Transcriptomic and Proteomic Reprogramming in the C. elegans Nucleotide Excision Repair Mutant xpa-1 (2013) Nucleic Acids Research 41(10):5368-81.

  4. Jobert, L., Skjeldam, H.K., Dalhus, B., Galashevskaya, A., Vaagbø, C.B., Bjørås, M. and Nilsen, H. The human base excision repair enzyme directly interacts with DKC1 and contributes to RNA quality control. (2013) Mol Cell. 49(2):339-45

  5. Tomazella, G., Kassahun, H., Nilsen, H., and Thiede, B. Quantitative proteome analysis reveals RNA processing factors as modulators of ionizing radiation-induced apoptosis in the C. elegans germline. (2012) J. Proteome Research, 11, 4277-88.

  6. Forthun, R.B., SenGupta, T., Skjeldam., H.K., Lindvall, J.M., McCormack, E., Gjertsen, B.T., and Nilsen, H., The Histone Demethylase UTX is required for Epigenetic Programming by Valproic Acid in Acute Myeloid Leukemia and C. elegans. (2012) PLoS One, 7(11):e48992

  7. Erdelyi, P., Borsos, E., Takacs-Vellai, Kovács, T., Kovács, A.L., Sigmond, T.., Hargitai, B., Pastor, L., SenGupta, T., Dengg, M., Pecsi, I., Toth, J., Nilsen, H., Vertessy, G.B., and Vellai, T. Shared transcriptional control of autophagy and apoptosis in C. elegans. (2011) Journal of Cell Science, 124, 1510-1518.

  8. Katarzyna D. Arczewska, Christian Baumeier, Tanima Sengupta, Henok Kassahun, Magnar Bjørås, Torbjørn Rognes, Jaroslaw T. Kusmierek, and Hilde Nilsen. Caenorhabditis elegans NDX-4 is a MutT-type enzyme that contributes to genomic stability. (2011) DNA repair, 10, 176-187.

  9. Skjeldam, H., Kassahun, H., Fensgård, Ø., SenGupta, T., Babaie, E., Lindvall, J.M., Arczewska, K.D. and Nilsen, H. Loss of C. elegans. UNG-1 Uracil-DNA glycosylase affects apoptosis in response to DNA damaging agents. (2010) DNA repair, 9, 861-870

  10. Fensgård, Ø., Kassahun, H., Bombik, I., Rognes, T., Lindvall, J., and Nilsen, H. A two-tiered compensatory response to loss of DNA repair modulates aging and stress response pathways. (2010) Aging, 2, 133-159.

  11. Dengg, M., Garcia-Muse, T., Salus, S.S., Gill, S.G., Ashcroft, N., Boulton, S.J, and Nilsen, H. (2006) Abrogation of the RAD-5/CLK-2 checkpoint leads to tolerance to base excision repair intermediates. EMBO Reports, 7, 1046-1051.

  12. Nilsen, H, Stamp, G., Andersen, S., Hrivnak, G., Krokan, H.E., Lindahl, T., and Barnes, D.E. (2003) Gene-targeted mice lacking the Ung uracil-DNA glycosylase develop B-cell lymphomas. Oncogene 22, 5381-5386.

  13. Nilsen, H., Lindahl, T., and Verreault, A. (2002) DNA base excision repair of uracil residues in reconstituted nucleosome core particles. EMBO J. 21, 5943-5952.

  14. Rada, C., Williams, G.T., Nilsen, H., Barnes, D.E., Lindahl, T., and Neuberger, M.S. (2002) Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Current Biology 12, 1748-1755.

  15. Nilsen, H., Haushalter, K.A., Robins, P., Barnes, D.E., Verdine, G.L. and Lindahl, T. (2001) Excision of deaminated cytosine from the vertebrate genome: role of the SMUG1 uracil-DNA glycosylase. EMBO J. 20, 4278-4286.

  16. Nilsen, H., Rosewell, I., Robins, P., Skjelbred, C.F., Andersen, S., Slupphaug, G., Daly, G., Krokan, H.E., Lindahl, T., Barnes, D.E. (2000) Uracil-DNA glycosylase (UNG)-deficient mice reveal a primary role of the enzyme during DNA replication. Mol. Cell 5, 1059-1065.

Published Dec. 3, 2014 9:32 AM - Last modified Mar. 29, 2016 10:20 AM

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