An accumulation of somatic and germline mutations is at the core of oncogenesis, and is often accelerated by deficiencies in genes responsible for maintaining genome integrity, such as p53 and the DNA repair proteins defective in Xeroderma pigmentosum (XP) and Bloom’s syndrome (BLM). The mechanisms involved in maintaining genome integrity and in preventing the propagation of mutant cells are extremely intricate. The DNA damage response (DDR) includes direct damage repair, recombinational repair, damage tolerance, damage-induced growth arrest and apoptosis. There is functional overlap between the different branches of the DDR, so that (for example) double-stranded DNA breaks can be repaired either by end-joining or by homologous recombination, depending on the circumstances. Because of their deficiencies in DDR, some cancer cells may be strongly dependent on the remaining pathways to maintain a functioning genome under conditions of rapid replication and chemical stress. These considerations suggest that inhibiting DDR processes may be a new avenue in cancer therapy. Our group aims to test this hypothesis and to promote the understanding of DDR processes using structural and chemical biology.
The second area of research focusses on the consequences of genetic instability: the impact of mutations on human disease. Vast studies in genetic associations and genomic sequencing are continuously adding to the list of mutations and variations associated with disease. In many cases, the roles of the mutated genes remain obscure. We initiate research on novel disease-linked genes by expressing and purifying the proteins, and attempting to decipher their functions by a combination of structural studies, biochemical assays, and the use of antibodies to locate the proteins in cells and tissues.
Newman JA, Cooper CD, Aitkenhead H, Gileadi O. (2015) Structure of the Helicase Domain of DNA Polymerase Theta Reveals a Possible Role in the Microhomology-Mediated End-Joining Pathway. Structure 23(12):2319-30.
doi: 10.1016/j.str.2015.10.014. PubMed PMID: 26636256; PubMed Central PMCID:PMC4671958.
Allerston CK, Lee SY, Newman JA, Schofield CJ, McHugh PJ, Gileadi O. (2015) The structures of the SNM1A and SNM1B/Apollo nuclease domains reveal a potential basis for their distinct DNA processing activities. Nucleic Acids Res.43(22):11047-60.
doi: 10.1093/nar/gkv1256. Epub 2015 Nov 17. PubMed PMID:26582912; PubMed Central PMCID: PMC4678830.
Newman JA, Savitsky P, Allerston CK, Bizard AH, Özer Ö, Sarlós K, Liu Y, Pardon E, Steyaert J, Hickson ID, Gileadi O. (2015) Crystal structure of the Bloom's syndrome helicase indicates a role for the HRDC domain in conformational changes. Nucleic Acids Res. 43(10):5221-35.
doi: 10.1093/nar/gkv373. Epub 2015 Apr 21. PubMed PMID: 25901030; PubMed Central PMCID: PMC4446433.
Pike AC, Gomathinayagam S, Swuec P, Berti M, Zhang Y, Schnecke C, Marino F, von Delft F, Renault L, Costa A, Gileadi O, Vindigni A. Human RECQ1 helicase-driven DNA unwinding, annealing, and branch migration: insights from DNA complex structures. Proc Natl Acad Sci U S A. (2015) 112(14):4286-91.
doi: 10.1073/pnas.1417594112. Epub 2015 Mar 23. PubMed PMID: 25831490; PubMed Central PMCID: PMC4394259.
Newman JA, Cooper CD, Roos AK, Aitkenhead H, Oppermann UC, Cho HJ, Osman R, Gileadi O. (2016) Structures of Two Melanoma-Associated Antigens Suggest Allosteric Regulation of Effector Binding. PLoS One. Feb 24;11(2):e0148762. doi: 10.1371/journal.pone.0148762. eCollection 2016. PubMed PMID: 26910052; PubMed Central PMCID: PMC4766014.