A5034029751- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Crystallography and molecular interactions
- DNA Repair Mechanisms
- PARP inhibition in cancer therapy
- Genomics and Chromatin Dynamics
- CRISPR and Genetic Engineering
- Cancer-related Molecular Pathways
- Microtubule and mitosis dynamics
- Enzyme Structure and Function
- 14-3-3 protein interactions
- Epigenetics and DNA Methylation
- Fungal and yeast genetics research
- Cervical Cancer and HPV Research
- Machine Learning in Materials Science
- RNA Research and Splicing
- Frailty in Older Adults
- Genital Health and Disease
- RNA and protein synthesis mechanisms
- Genetics and Neurodevelopmental Disorders
- Cell Image Analysis Techniques
- Biochemical and Molecular Research
- Advanced Nanomaterials in Catalysis
- Cancer Diagnosis and Treatment
- Cancer therapeutics and mechanisms
Queen Mary University of London
2023-2025
University of Sussex
2013-2024
University of Brighton
2024
Healthcare Quality Improvement Partnership
2024
Cancer Research UK
2013-2023
Philips (Finland)
2021
In mitosis, cells inactivate DNA double-strand break (DSB) repair pathways to preserve genome stability. However, some early signaling events still occur, such as recruitment of the scaffold protein MDC1 phosphorylated histone H2AX at DSBs. Yet, it remains unclear whether these are important for maintaining stability during mitosis. Here, we identify a highly conserved protein-interaction surface in that is by CK2 and recognized DNA-damage response mediator TOPBP1. Disruption MDC1-TOPBP1...
53BP1 plays multiple roles in mammalian DNA damage repair, mediating pathway choice and facilitating double-strand break repair heterochromatin. Although it possesses a C-terminal BRCT2 domain, commonly involved phospho-peptide binding other proteins, initial recruitment of to sites depends on interaction with histone post-translational modifications—H4K20me2 H2AK13/K15ub—downstream the early γH2AX phosphorylation mark damage. We now show that, contrary current models, 53BP1-BRCT2 domain...
Coordination of the cellular response to DNA damage is organised by multi-domain ‘scaffold’ proteins, including 53BP1 and TOPBP1, which recognise post-translational modifications such as phosphorylation, methylation ubiquitylation on other are themselves carriers regulatory signals. Here we show that checkpoint regulating S-phase entry controlled a phosphorylation-dependent interaction TOPBP1. BRCT domains TOPBP1 selectively bind conserved phosphorylation sites in N-terminus 53BP1. Mutation...
Abstract Activation of the replicative Mcm2-7 helicase by loading GINS and Cdc45 is crucial for replication origin firing, as such faithful genetic inheritance. Our biochemical structural studies demonstrate that activator interacts with TopBP1 through two separate binding surfaces, first involving a stretch highly conserved amino acids in TopBP1-GINI region, second surface on TopBP1-BRCT4. The surfaces bind to opposite ends A domain subunit Psf1. Mutation analysis reveals either...
TOPBP1 and its fission yeast homologue Rad4, are critical players in a range of DNA replication, repair damage signalling processes. They composed multiple BRCT domains, some which bind phosphorylated motifs other proteins. thus act as multi-point adaptors bringing proteins together into functional combinations, dependent on post-translational modifications downstream cell cycle signals. We have now structurally and/or biochemically characterised sufficient number high-affinity complexes for...
The RAD9-RAD1-HUS1 (9-1-1) clamp forms one half of the DNA damage checkpoint system that signals presence substantial regions single-stranded arising from replication fork collapse or resection double strand breaks. Loaded at 5'-recessed end a dsDNA-ssDNA junction by RAD17-RFC loader complex, phosphorylated C-terminal tail RAD9 subunit 9-1-1 engages with mediator scaffold TOPBP1 which in turn activates ATR kinase, localised through interaction its constitutive partner ATRIP RPA-coated ssDNA....
During the human papillomavirus 16 (HPV16) life cycle, E2 protein interacts with host factors to regulate viral transcription, replication, and genome segregation/retention. Our understanding of partner proteins their roles in functions remains incomplete. Here we demonstrate that CK2 phosphorylation on serine 23 promotes interaction TopBP1
RIF1 is a multifunctional protein that regulates DNA replication and repair. RIF1-deficient cells are hypersensitive to stress. Of the two alternatively spliced isoforms, called RIF1-Short RIF1-Long, RIF1-Long isoform more capable than in supporting cell recovery from Examining stress resistance mechanisms specific we find prolonged unexpectedly induces interaction of with BRCA1. Mechanistically, phosphorylated SPKF motif unique binds tandem BRCT domain BRCA1-RIF1-Long strongly...
CHK1 is a protein kinase that functions downstream of activated ATR to phosphorylate multiple targets as part intra-S and G2/M DNA damage checkpoints. Its role in allowing cells survive replicative stress has made it an important target for anti-cancer drug discovery. Activation by depends on their mutual interaction with CLASPIN, natively unstructured interacts through cluster phosphorylation sites its C-terminal half. We have now determined the crystal structure domain bound high-affinity...
Abstract Activation of the replicative Mcm2-7 helicase by loading GINS and Cdc45 is crucial for replication origin firing, as such faithful genetic inheritance. Our biochemical structural studies demonstrate that activator interacts with TopBP1 through two separate binding surfaces, first involving a stretch highly conserved amino acids in TopBP1-GINI region, second surface on TopBP1-BRCT4. The surfaces bind to opposite ends A domain subunit Psf1. Mutation analysis reveals either...
Abstract The BTRR (BLM/TOP3A/RMI1/RMI2) complex resolves various DNA replication and recombination intermediates to suppress genome instability. Alongside PICH, they target mitotic intertwinements, known as ultrafine bridges, facilitating chromosome segregation. Both BLM PICH undergo transient hyper-phosphorylation, but the biological significance of this remains elusive. Here, we uncover that during early mitosis, multiple protein kinases act together strictly constrain for protection...
<title>Abstract</title> The BTRR (BLM/TOP3A/RMI1/RMI2) complex resolves various DNA replication and recombination intermediates to suppress genome instability. Alongside PICH, they target mitotic intertwinements, known as ultrafine bridges, facilitating chromosome segregation. Both BLM PICH undergo transient hyper-phosphorylation, but the biological significance of this remains elusive. Here, we uncover that during early mitosis, multiple protein kinases act together strictly constrain for...
Abstract Mitotic DNA double-strand breaks (DSBs) accumulate in response to replication stress or BRCA1/2 deficiency posing a significant threat genome stability as repair by non-homologous end-joining (NHEJ) and homologous recombination (HR) is inactivated mitosis. cells instead rely on the mechanisms of microhomology mediated (MMEJ) mitotic synthesis (MiDAS). However, how these pathways are regulated mitosis remains unknown. Here we reveal CIP2A-TOPBP1 complex facilitates recruitment SMX...
Abstract During the human papillomavirus 16 (HPV16) life cycle, E2 protein interacts with host factors to regulate viral transcription, replication and genome segregation/retention. Our understanding of partner proteins their roles in functions remains incomplete. Here, we demonstrate that CK2 phosphorylation on serine 23 promotes interaction TopBP1 vitro vivo , is phosphorylated this residue during HPV16 cycle. We investigated consequences mutating functions. E2-S23A activates represses...