DNA damage response and neurodegenerative diseases
Human cells repair thousands of DNA lesions daily. The majority of lesions arise from the intrinsic chemical instability of DNA and include single-strand breaks and base modifications. In non-proliferating cells (for example, post-mitotic neurons) damaged DNA bases and single-strand breaks can block transcription, leading to mutations, cell death and disease. In particular, defects in DNA repair are often linked to progressive neurological disorders (X-linked mental retardation, Ataxia Telangiectasia, Seckel syndrome etc.), although their precise roles in the neurological phenotypes remain elusive.
The successful applicant will investigate the mechanistic links between deficiencies in DNA repair and neurodegeneration using cutting-edge techniques. These include differentiation of human induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) into a neural lineage, CRISPR/Cas9 gene knockout and editing, engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP), confocal microscopy, mass spectrometry etc.
1. Khoronenkova SV & Dianov GL (2015) ATM prevents DSB formation by coordinating SSB repair and cell cycle progression. Proc. Natl. Acad. Sci. 112, 3997-4002.
2. Khoronenkova SV & Dianov GL (2013) USP7S-dependent inactivation of Mule regulates DNA damage signaling and repair. Nucl. Acids Res. 41, 1750-1756.
3. Khoronenkova SV, Dianova II, Edelmann MJ, Kessler BM, Parsons JL, & Dianov GL (2012) ATM-dependent down-regulation of USP7/HAUSP by PPM1G activates p53 response to DNA damage. Mol. Cell 45, 801-813.