Dr. Andrei L Okorokov
- 020 7679 0959 / a.okorokov@ucl.ac.uk

Chromosome Stability Group

Our group’s research programme brings together cell, molecular and structural biology of the protein machineries and signalling pathways controlling and maintaining the integrity of our chromosomes. We have three main areas of research interest:

p53 tumour suppressor

We are exploring how cellular tumour suppressors coordinate DNA metabolism processes. Our research focuses on the p53 protein, a major tumour suppressor activated in response to DNA damage. This protein can induce either cell growth arrest and DNA repair, or cell death. Our recently solved structures of the complete p53 tetramer and p53 in complex with its specific DNA target outlay structure-function relationship principles for this paramount “Guardian of Genome”.

SIRT1 and chromosomal maintenance

Human SIRT1 is a NAD+-dependent protein deacetylase that belongs to the conserved Sirtuin family. It participates in cellular controls of gene expression, metabolism, genomic stability and anti-ageing. Our recent work demonstrated that human SIRT1 is also an essential contributor to chromosomal condensation during mitosis. Lack of SIRT1 in human cells leads to improper chromosome condensation, chromosome "bridges" and breakage, and aneuploidy, indicating that SIRT1 activity in mitosis is vital for chromosome stability.

DNA replication

The first line of the cells’ defence lies at the very beginning of the DNA replication process. Part of our research is focused on the assembly and function of the human DNA replication protein machinery, in particular the process of DNA replication initiation. We are currently working on the human DNA replication initiation protein MCM10, and are trying to elucidate its structure-function relationship using a multidisciplinary approach.

Selected publications

Fatoba ST, Okorokov AL. (2011) Human SIRT1 associates with mitotic chromatin and contributes to chromosomal condensation. Cell Cycle. 10(14):2317-22.

Aramayo R, Sherman MB, Brownless K, Lurz R, Okorokov AL, Orlova EV. (2011) Quaternary structure of the specific p53-DNA complex reveals the mechanism of p53 mutant dominance. Nucleic Acids Res. Jul 14. [Epub ahead of print]; free access

Okorokov AL, Chaban YL, Bugreev DV, Hodgkinson J, Mazin AV, Orlova EV. (2010) Structure of the hDmc1-ssDNA filament reveals the principles of its architecture. PLoS One. Jan 6;5(1):e8586. free access

Okorokov AL, Waugh A, Hodgkinson J, Murthy A, Kyung Hong H, Leo E, Sherman M, Stoeber K, Orlova EV and Wiliams GH. (2007) Hexameric ring structure of human MCM10 DNA replication factor. EMBO Reports 8:925-930. free access

Okorokov AL, Sherman MB, Plisson C, Grinkevich V, Sigmundsson K, Selivanova G, Milner J, Orlova EV. (2006) The structure of p53 tumour suppressor protein reveals the basis for its functional plasticity. EMBO Journal 25:5191-5200. free access

Bochkareva E, Kaustov L, Ayed A, et al. (2005) Single-stranded mimicry in the p53 transactivation domain interaction with replication protein A.  Proc. Natl. Acad. Sci. USA 102:15412-15417. free access

Okorokov AL, Orlova EV, Kingsbury SR, et al. (2004) Molecular structure of human geminin. Nature Struct. Mol. Biol. 11:1021-1022.

te Poele RH, Okorokov AL, Jardine L, Cummings J, Joel SP. (2002) DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res. 62(6):1876-83. free access

Okorokov AL, Milner J. (1999) An ATP/ADP-dependent molecular switch regulates the stability of p53-DNA complexes. Mol Cell Biol. 19(11):7501-10. free access

Academic Career

Funding

BBSRC, MRC