NPIF Innovation Fellowship
Lead Research Organisation:
MRC Laboratory of Molecular Biology
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
During replication, DNA is unwound to expose single strands as a template for DNA synthesis. However, the propensity of single stranded DNA to form secondary structures poses a challenge to the smooth progression of the replication fork. Certain sequences are particularly prone to secondary structure formation, for instance G quadruplexes (G4) and triple helix forming DNA (H-DNA). Accumulating evidence suggests these structures form readily during replication in vertebrate cells, but are actively countered by a complex network of enzymes. Over 700,000 sites in the human genome are capable of G4 formation, so these structures pose challenges to replication forks potentially as frequently as naturally occurring DNA damage. Moreover, failure to maintain processive replication at secondary structures is associated with both genetic and epigenetic instability. However, the full range factors that promote secondary structure resolution during vertebrate replication is not known, and the in vivo coordination of existing enzymes and the forms of secondary structures upon which they act is also poorly understood. This project will investigate this area using a combination of RNAseq in mutants of known factors, and which have had secondary structures artificially inserted, as well as techniques that identify the location of R-loops (DNA-RNA hybrid triple helixes that may be formed in association with other secondary structures) to provide a comprehensive view of how these challenging DNA replication impediments occur and how they are handled. This will be ultimately important for understanding the circumstances under which structure-forming DNA sequences contribute to human pathology, for example in inherited syndromes, such as Werner or Bloom syndrome, or in cancer, in which replication stress may lead to widespread dysregulation of gene expression.
People |
ORCID iD |
Publications
Eldridge CB
(2020)
A p53-Dependent Checkpoint Induced upon DNA Damage Alters Cell Fate during hiPSC Differentiation.
in Stem cell reports
Ferreira ACF
(2021)
RORa is a critical checkpoint for T cell and ILC2 commitment in the embryonic thymus.
in Nature immunology
Švikovic S
(2019)
R-loop formation during S phase is restricted by PrimPol-mediated repriming.
in The EMBO journal
Description | Seminar on Transcriptome analysis |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Yearly seminars in how to use computational resources developed during this fellowship to analyse your data |
Year(s) Of Engagement Activity | 2019,2020 |