New frontiers in RNA metabolism: The biology of RNA kinases and RNA ligases

Referent: Javier Martinez, IMBA, Austria
Zeit:  Mittwoch, 5 März 2014;  15:00 Uhr
Ort: MPI Auditorium

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Speaker: Javier Martinez
Affiliation:  IMBA, Austria
Date & Time:  Wednesday,  March 5, 2014 @ 3:00 pm
Location: MPI Auditorium

RNA metabolic pathways relying on ligation and phosphorylation of RNA molecules have remained unexplored, hampered by the absence of putative enzymatic factors. Combining activity-guided protein purification and RNAi of candidate genes we have revealed and biochemically characterized CLP1 as an RNA-kinase within the tRNA splicing endonuclease (S. Weitzer & J. Martinez, 2007) and HSPC117/RTCB as the catalytic subunit of the long-sought human tRNA ligase (J. Popow et al. 2011). Recently, using clusters of Orthologous Groups for euKaryotic genomes – KOGs – we identified Archease as an essential factor that licenses HSPC117/RTCB for multiple catalytic cycles.

The in vivo function of these RNA processing enzymes is being investigated through the analysis of conditional knockout and knock-in mice. This approach has so far led to the discovery of a novel tyrosine-tRNA fragment in mice expressing a kinase-dead version of CLP1 (K127A) which develop a progressive motor-neuron disease via p53 hyperphosphorylation (T. Hanada et al. 2013). More recently, in collaboration with Josef Penninger (IMBA, Vienna) and Jim Lupski (Baylor College of Medicine, Texas) we characterized families with a homozygous mutation (R140H) in CLP1. All affected individuals develop progressive and severe motor-sensory defects and exhibit microcephaly and defined facial dysmorphism. The CLP1 mutation in the patients results in near complete loss of interaction with the tRNA splicing endonuclease complex, severely reduced pre-tRNA cleavage and RNA kinase activity, and the accumulation of several tRNA-introns.

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