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Subject of the thesis

Characterization of novel metalloproteases involved in DNA damage repair

Published on 25 January 2019
DNA is the central molecule of life. Every day DNA is challenged by thousands of lesions, which can compromise the integrity of genetic information. Repair of abnormal DNA-protein complexes and covalent DNA–protein crosslinks (DPCs) is particularly challenging. Accumulating data suggest that proteolytic enzymes are involved in DNA repair by degrading the protein component of DPCs and making them amenable for classic DNA repair pathways. However, the identity of these proteases remained obscure. Recently, we and others have described a novel yeast protease, Wss1, which degrades problematic proteins and DPCs on the chromatin. Wss1 is required for clearing toxic topoisomerase TopI-DNA complexes, UV- and formaldehyde-produced DPCs, and aberrant chromatin conjugates induced by a mutation of SUMO gene. This suggests a new mechanism of DPC repair that involves direct proteolysis of chromatin proteins by specialized proteases. Notably, this pathway seems to be conserved through evolution. Indeed, higher Eukaryotes has Spartan proteins (SprT family), which may have a common ancestry with Wss1-like metalloproteases (WLM-family) in yeast. Although sequence alignment places Spartans in a distinct SprT family, our analysis suggests that the structure of SprT is very similar to the WLM domain, both belonging to the minigluzincin superfamily of the proteases. Thus, Spartan may be a functional protease that removes the stalled chromatin components. The goal of Ph.D. project is to characterize biochemically and structurally these novel metalloproteases implicated in the repair of DNA damage.

Miscellaneous information
• Recommended Master level training.
• Biochemistry, Molecular Biology, Structural biology
• Date requested for the start of the thesis: October 01, 2017
• Contact person (Thesis supervisor):
Maxim Balakirev
Laboratoire Biologie à Grande Échelle
17 avenue des Martyrs
38054 Grenoble Cedex 9

More informations on the web page of the team.