Research
Structural biology, CryoEM, Alphafold, DNA replication, DNA repair, Cancer
Interests
DNA replication must occur once, and only once, during each cell cycle. In eukaryotic cells this process is carried out by the replisome, a massive protein machine with many components. The MCM helicase is loaded at origins of replication in an inactive confirmation and must be converted to its active form by a highly coordinated process of events for individual origins to fire and for replication to successfully progress. This is driven by the recruitment of additional protein factors and much of this control is aided by scaffold proteins, such as TOPBP1, bringing the required factors together at the right time.
As well as having to be duplicated, the DNA in our cells is subject to damage every day and must be repaired to maintain genomic stability. DNA repair also requires the coordinated recruitment of multiple protein factors to sites of DNA damage to first recognise, stabilise, mark, and finally repair the damage. Again, large scaffold proteins, including TOPBP1, play important roles in many of these processes.
Research in our group explores the mechanistic details of these processes, with a focus on TOPBP1, through a combination of structural biology (e.g. cryogenic electron microscopy, x-ray crystallography and in silico modelling), biophysical (e.g. fluorescence polarisation and isothermal calorimetry) and other protein and nucleic acid biochemical techniques.
Publications

Publications of specific relevance to the Centre for Molecular Cell Biology
2024
TopBP1 utilises a bipartite GINS binding mode to support genome replicationDay M, Tetik B, Parlak M, Almeida-Hernández Y, Räschle M, Kaschani F, Siegert H, Marko A, Sanchez-Garcia E, Kaiser M, Barker IA, Pearl LH, Oliver AW and Boos D
Nature Communications,
Springer Nature vol. 15 (1)
27-02-20242022
Structure of the human RAD17–RFC clamp loader and 9–1–1 checkpoint clamp bound to a dsDNA–ssDNA junctionDay M, Oliver AW and Pearl LH
Nucleic Acids Research,
Oxford University Press (OUP) vol. 50 (14), 8279-8289.
12-07-20222021
Phosphorylation-dependent assembly of DNA damage response systems and the central roles of TOPBP1Day M, Oliver AW and Pearl LH
DNA Repair,
Elsevier vol. 108
29-09-2021
CK2 Phosphorylation of Human Papillomavirus 16 E2 on Serine 23 Promotes Interaction with TopBP1 and Is Critical for E2 Interaction with Mitotic Chromatin and the Viral Life CyclePrabhakar AT, James CD, Das D, Otoa R,
Day M, Burgner J, Fontan CT, Wang X, Glass SH, Wieland A, Donaldson MM, Bristol ML, Li R, Oliver AW, Pearl LH, Smith BO and Morgan IM
Mbio,
American Society For Microbiology vol. 12 (5), 10.1128/mbio.01163-10.1128/mbio.01121.
21-09-2021
Structural basis for recruitment of the CHK1 DNA damage kinase by the CLASPIN scaffold proteinDay M, Parry-Morris S, Houghton-Gisby J, Oliver AW and Pearl LH
Structure,
Elsevier vol. 29 (6), 531-539.e3.
30-03-20212019
Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpointBigot N,
Day M, Baldock RA, Watts FZ, Oliver AW and Pearl LH
Elife,
Elife vol. 8
28-05-2019
MDC1 Interacts with TOPBP1 to Maintain Chromosomal Stability during MitosisLeimbacher P-A, Jones SE, Shorrocks A-MK, de Marco Zompit M,
Day M, Blaauwendraad J, Bundschuh D, Bonham S, Fischer R, Fink D, Kessler BM, Oliver AW, Pearl LH, Blackford AN and Stucki M
Molecular Cell,
Elsevier vol. 74 (3), 571-583.e8.
18-03-20192018
BRCT domains of the DNA damage checkpoint proteins TOPBP1/Rad4 display distinct specificities for phosphopeptide ligandsDay M, Rappas M, Ptasinska K, Boos D, Oliver AW and Pearl LH
Elife,
Elife vol. 7
08-10-20182015
ATM Localization and Heterochromatin Repair Depend on Direct Interaction of the 53BP1-BRCT2 Domain with γH2AXBaldock RA,
Day M, Wilkinson OJ, Cloney R, Jeggo PA, Oliver AW, Watts FZ and Pearl LH
Cell Reports,
Elsevier vol. 13 (10), 2081-2089.
25-11-20152013
Phosphorylation-Dependent Assembly and Coordination of the DNA Damage Checkpoint Apparatus by Rad4TopBP1Qu M, Rappas M, Wardlaw CP, Garcia V, Ren J-Y,
Day M, Carr AM, Oliver AW, Du L-L and Pearl LH
Molecular Cell,
Elsevier vol. 51 (6), 723-736.
01-09-2013