Further in vivo characterization of the mutant and polymorphic DNA ligase IV proteins found in LIG4 patients

Project leader: Miroslav Chovanec
Project duration: 2006 - 2009

Since DNA double-strand breaks (DSB) can initiate processes leading to mutagenesis, tumorigenesis and death, their repair is essential to maintain genome stability and cell viability. The main pathway for the repair of DSB in mammals is non-homologous end-joining, in which the DNA ligase IV/XRCC4 complex (LX) is the key player. Recently, five LIG4 patients were reported, each with hypomorphic mutations in DNA ligase IV and one with two linked polymorphisms. All mutant and polymorphic changes were already characterized in vitro, although in vivo data are rather limited due to a lack for sensitive in vivo assays in mammals. We intend to further characterize impact of the mutant and/or polymorphic changes on LX function in vivo. This will be achieved by heterologous expression of the mutant and polymorphic LX in S. cerevisiae and by monitoring of efficiency and accuracy of DSB rejoing in well-defined systems. Moreover, impact of mutant and polymorphic LX on chromosomal instability will be examined.

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