Svetlana Khoronenkova

DNA repair 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. Unrepaired lesions can obstruct DNA replication, leading to mutations and toxic DNA double-strand breaks. In non-proliferating cells (for example, post-mitotic neurons) damaged DNA bases and single-strand breaks can block transcription, leading to cell death and disease. Although defects in DNA repair are often linked to progressive neurological disorders, their precise roles in the neurological phenotypes remain elusive.

To discover molecular mechanisms by which DNA repair deficiencies underpin neurological diseases, we use in vitro systems reconstituted with purified proteins, mammalian cell culture models, and human induced pluripotent stem cells (iPSCs). Biochemical and molecular biological techniques that we use include CRISPR, ChIP, real-time PCR, confocal microscopy, mass spectrometry etc.

Our work is supported by the Royal Society and the Wellcome Trust.

Research objectives

  • Unravel molecular mechanisms by which mutations in DNA damage response proteins, such as ATM kinase, lead to progressive neurodegeneration.

  • Determine how DNA damage and repair contributes to disease progression in the brain.

  • Discover whether DNA repair deficiencies that lead to different neurodegenerative diseases share a common mechanism.

  • Identify novel DNA damage response proteins required for the maintenance of homeostasis in the brain.

Key publications

Talbot EJ, Joshi L, Thornton P, Dezfouli M, Tsafou K, Perkinton M, Khoronenkova SV (2023). The cGAS-STING pathway regulates microglial chemotaxis in genome instability. bioRxiv 2023.08.25.554654. doi: 10.1101/2023.08.25.554654

Bourseguin J, Wen C, Talbot E, Hardy L, Lai J, Jeffries AM, Lodato MA, Lee EA, Khoronenkova SV (2022). Persistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunction. Nucleic Acids Res., 50(5):2700-2718. doi: 10.1093/nar/gkac104

Khoronenkova SV, Dianov GL (2015). ATM prevents DSB formation by coordinating SSB repair and cell cycle progression. Proc. Natl. Acad. Sci. U.S.A., 112(13):3997-4002. doi: 10.1073/pnas.1416031112

Khoronenkova SV, Dianov GL (2013). USP7S-dependent inactivation of Mule regulates DNA damage signalling and repair. Nucleic Acids Res., 41(3):1750-1756. doi: 10.1093/nar/gks1359

Khoronenkova SV, Dianova II, Ternette N, Kessler BM, Parsons JL, Dianov GL (2012). ATM-dependent downregulation of USP7/HAUSP by PPM1G activates p53 response to DNA damage. Mol. Cell, 45(6):801-813. doi: 10.1016/j.molcel.2012.01.021