Cell cycle control of DNA repair in lymphoid cells

Summary

PhD opportunity in an NHMRC-funded group to determine how cell cycle determines the fidelity of DNA repair in activated B cells in vivo.

Supervisor(s)

Dr Chris Jolly

Research Location

Camperdown - Centenary Institute

Program Type

Masters/PHD

Synopsis

The activation of B cells during immune responses induces antibody affinity maturation and the switching of antibody isotypes. These processes lead to the production of high affinity antibodies able to penetrate tissues from which IgM (the starting isotype) is excluded. Both processes depend on the enzyme activation-induced cytidine deaminase (AID), which damages Ig target DNA, recruiting mutagenic DNA repair. Antibody gene mutation is essential for optimal humoral immunity, but comes at a cost: AID-induced damage in “off-target” genes induces the Ig-translocations that typify most, if not all, adult B cell cancers. My group seeks to understand why AID-induced DNA damage is repaired with low fidelity, when spontaneous forms of the same damage in other tissues are generally repaired with high fidelity. We have developed a unique approach: by fusing cell-cycle regulated motifs (“degrons”) to recombinant DNA repair enzymes (or enzyme agonists) expressed in mouse B cells in vivo, we have shown that the cell cycle timing of AID-induced DNA repair determines whether repair is mutagenic or faithful (Sharbeen et al. 2012 Journal of Experimental Medicine 209:965-74).  This project will extend our findings to map when in the cell cycle DNA repair events induced by AID occur, and how AID-induced repair can be manipulated to prevent oncogenic translocations.

Additional Information

The DNA Repair Group at the Centenary Institute is a focussed basic research group with a track record of obtaining peer-reviewed funding and of publication in high impact journals. Chris Jolly has been the primary supervisor for three PhD students, who have all published their research in peer-reviewed journals, and for seven Honours students, who have almost all been awarded first class degrees.

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Keywords

DNA damage, DNA repair, Activation-induced cytidine deaminase, B cells, Immunology, Cancer, molecular biology, transgenic mice, cell cycle, ubiquitin, in vivo, antibodies, somatic hypermutation, uracil

Opportunity ID

The opportunity ID for this research opportunity is: 1713