Molecular Medicine Partnership Unit

 

Diseases of mRNA metabolism

Matthias Hentze and Andreas Kulozik
Matthias Hentze and Andreas Kulozik


Andreas E. Kulozik and Matthias W. Hentze

Project Summary

Our team focuses on basic and translational aspects of mRNA metabolism in common diseases such as the hemoglobin disorders, thrombosis, inflammation and childhood cancer. One specific aspect of this general theme is the mechanism of nonsense-mediated decay (NMD), one of the cell’s key mRNA quality control pathways to limit the synthesis of faulty proteins. The other specific aspect is the regulation of mRNA 3’ end processing and its impact in response to stress.

 

Background

The entry points into these two major projects of the group have been the detailed clinical analysis of two common hematological disorders, ß-thalassemia and thrombophilia, respectively. Interestingly, it is now becoming apparent that the principles that have been uncovered by the analysis of these two model conditions are applicable more generally. Furthermore, the results of these projects have illustrated that the detailed analysis of unexplained medical phenomena can result in the identification and characterization of previously unrecognized basic biological mechanisms with broad implications. With a continued focus on the “disease mechanisms aspect” of our work, future work will build on the maturity that this work has reached towards more translational aspects.

 

Goals

The overall goals of our projects relate to a mechanistic understanding of RNA quality control by NMD and of regulated 3’ processing. Building on this, we aim to translate the mechanistic knowledge into an understanding of medically relevant pathways that lead to common human pathology. As a long term goal, we hope to identify steps of the molecular pathogenesis of RNA processing that allow us to develop strategies for therapeutic interventions.

 

Research Focus 1

Nonsense mediated decay (NMD)

NMD targets mRNAs with premature translation stop codons for rapid degradation thus limiting the synthesis of potentially harmful but also of potentially useful C-terminally truncated proteins. NMD thus contributes to the fidelity of gene expression but is also involved in regulatory circuits of alternatively spliced RNAs. The key mechanistic question of NMD is how an abnormal mRNA is recognized, which differs from the normal mRNA only in the length of its open reading frame but not in its overall structure. One of the key medical questions in the NMD field is the development of therapeutic strategies of important genetic disorders which benefit from the synthesis of C-terminally truncated proteins (e.g. Duchenne’s Muscular Dystrophy).
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Research Focus 2

3‘end processing of prothrombin mRNA and predisposition to thrombosis (thrombophilia).

It has recently been recognized that 3’ end processing is a process that the cell can regulate to achieve both, differences in the structure and also the quantity of RNA expression. We have recently identified a novel class of genes, with prothrombin (the key regulator of blood coagulation) as a prototype, which is characterized by a specific architecture of the 3’ processing signal that interacts with 3’ end processing proteins and splicing proteins in an unexpected fashion to achieve regulated RNA processing. We are currently analyzing how this novel mechanism of regulated RNA processing contributes to important pathways of human physiology and pathology.
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Important Publications

Opens external link in new window5-azacytidine inhibits nonsense-mediated decay in a MYC-dependent fashion.
Bhuvanagiri M, Lewis J, Putzker K, Becker JP, Leicht S, Krijgsveld J, Batra R, Turnwald B, Jovanovic B, Hauer C, Sieber J, Hentze MW, Kulozik AE.
EMBO Mol Med. 2014 Oct 15. pii: e201404461. doi: 10.15252/emmm.201404461.

 

Opens external link in new windowmRNA 3'end processing: A tale of the tail reaches the clinic
Ina Hollerer, Kerstin Grund, Matthias W. Hentze, Andreas E. Kulozik
EMBO Mol Med. 2014 Jan 1;6(1):16-26. doi: 10.1002/emmm.201303300.

 

Opens external link in new windowPathologies at the nexus of blood coagulation and inflammation: thrombin in hemostasis, cancer, and beyond.
Danckwardt S, Hentze MW, Kulozik AE.
J Mol Med (Berl). 2013 Aug 17.

 

Opens external link in new windowTwo mammalian MAGOH genes contribute to exon junction complex composition and nonsense-mediated decay.
Singh KK, Wachsmuth L, Kulozik AE, Gehring NH.
RNA Biol. 2013 Aug 1;10(8):1291-1298. Epub 2013 Jul 23

 

Opens external link in new windowNotch1 activation clinically antagonizes the unfavorable effect of pten inactivation in bfm-treated children with precursor t-cell acute lymphoblastic leukemia.
Bandapalli OR, Zimmermann M, Kox C, Stanulla M, Schrappe M, Ludwig WD, Koehler R, Muckenthaler MU, Kulozik AE
Haematologica 2013 Jun;98:928-936

Opens external link in new windowKrebs, Blutgerinnung und Stress –  eine ungewöhnliche Ménage-à-trois
Matthias W. Hentze und Andreas E. Kulozik
Spektrum der Wissenschaft, Juli 2012

 

Opens external link in new windowStay tuned: miRNA expression and nonsense-mediated decay in brain development. 
Kulozik AE.
Mol Cell. 2011 May 20;42(4):407-8.
Initiates file downloadpdf

 

Opens external link in new windowMechanism of escape from nonsense-mediated mRNA decay of human {beta}-globin transcripts with nonsense mutations in the first exon.
Neu-Yilik G, Amthor B, Gehring NH, Bahri S, Paidassi H, Hentze MW, Kulozik AE.
RNA. 2011 May;17(5):843-54. Epub 2011 Mar 9

 

Opens external link in new windowp38 MAPK controls prothrombin expression by regulated RNA 3' end processing.
Danckwardt S, Gantzert AS, Macher-Goeppinger S, Probst HC, Gentzel M, Wilm M, Gröne HJ, Schirmacher P, Hentze MW, Kulozik AE.
Mol Cell. 2011 Feb 4;41(3):298-310.

 

Opens external link in new windowALL can be separated from NOTCH pathway activation by FBXW7 loss of function. 
Kox, C, M. Zimmermann, M. Stanulla, M. S. Leible, M. Schrappe, W.-D. Ludwig, M. Muckenthaler, A.E. Kulozik. 
Leukemia. 2010 Dec;24(12):2005-13. Epub 2010 Oct 14

 

Opens external link in new windowTaking childhood leukemia personally.
Kulozik AE.
Blood. 2010 Dec 2;116(23):4737-8.

 

Opens external link in new windowNMD: RNA biology meets human genetic medicine. 
Bhuvanagiri, M, A. M. Schlitter, M. W. Hentze, A.E. Kulozik
Biochemical Journal (2010) Aug 27;430(3):365-77

 

Opens external link in new windowDisassembly of exon junction complexes by PYM. 
Gehring N.H., S. Lamprinaki, A.E. Kulozik, M.W. Hentze. 
Cell. 2009 May 1;137(3):536-48.

Opens external link in new windowThe hierarchy of exon-junction complex assembly by the spliceosome explains key features of mammalian nonsense-mediated mRNA decay. 
Gehring NH, Lamprinaki S, Hentze MW, Kulozik AE. 
PLoS Biol. 2009 May 26;7(5):e1000120. Epub 2009 May 26.

Opens external link in new windowInteractions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways
Ivanov P., N. Gehring, J. Kunz, M.W. Hentze, A.E. Kulozik. 
EMBO Journal 27, 736–747 (2008).

Opens external link in new window3' end mRNA processing: Molecular mechanisms and implications for health and disease
Danckwardt, S., M.W. Hentze, A.E. Kulozik. 
EMBO Journal 27, 482–498 (2008).

Opens external link in new windowSplicing factors stimulate polyadenylation via USEs at non-canonical 3’ end formation signals
Danckwardt, S., I. Kaufmann, M. Gentzel, K. Förstner, A.S. Gantzert, N.H. Gehring, G. Neu-Yilik, P. Bork, W. Keller, M. Wilm, M.W. Hentze, A.E. Kulozik. 
EMBO Journal 26:2658-69 (2007)

Opens external link in new windowAll previous publications

 

Opens external link in new windowResearch group's MMPU link to EMBL web page

 

 

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