Cellular and Pathological Responses to Chromosome DNA Single-Strand Breaks
Lead Research Organisation:
University of Sussex
Department Name: Sch of Life Sciences
Abstract
My laboratory is focused on understanding how breaks in the genetic material (DNA) can lead to neurodegeneration. The proposed work will address exciting new hypotheses that have arisen during my current research Programme concerning the mechanism/s by which DNA single-strand breaks are sensed and repaired, and exciting and unexpected novel physiological roles for the pathway that repairs these breaks (single-strand break repair). We have also uncovered a mechanism by which unrepaired single-strand breaks trigger neurodegeneration, providing not only the first molecular explanation of this pathological event but also opening up possible avenues for therapeutic intervention. We plan to pursue these novel discoveries in the new Programme of work proposed here. Whilst we are focusing on experimental models of rare genetic diseases to address our scientific questions, the relevance of this work may extend to degenerative diseases observed in the normal ageing population. This is because single-strand breaks are the commonest DNA lesions arising in cells and are induced by oxidative stress; an etiological factor implicated in ageing.
Technical Summary
My laboratory is focused on understanding the molecular mechanism/s of DNA strand break repair and their links to human disease. The proposed work will address exciting new hypotheses that have arisen during my current research Programme concerning both the mechanism/s by which DNA single-strand breaks are repaired and the link between this process and neurological disease. Whilst we are focusing on experimental model systems in which single-strand break repair is defective to address these questions, the relevance of this work may extend to neurodegenerative disease in the normal ageing population. This is because single-strand breaks are the commonest DNA lesions arising in cells and are induced by oxidative stress; an etiological factor implicated in normal human ageing. In summary, our recent work has identified novel components of single-strand break sensing by by poly(ADP-ribose) polymerase enzymes. We have also identified new and unexpected putative roles for the single-strand break repair pathway beyond its canonical role in global genome repair that are linked to transcription and/or RNA splicing. In addition, we have identified novel gene mutations associated with single-strand break repair-defective neurodegenerative disease and uncovered a molecular mechanism by which unrepaired single-strand breaks trigger neurodegeneration; providing not only the first molecular explanation of this pathological event but also raising exciting possibilities concerning therapeutic intervention. We will now pursue the new questions and hypotheses arising from our recent work in the research Programme described here, using a combination of biochemical, cellular, and physiological model systems.
Planned Impact
The discovery science in this Programme is firmly embedded in the MRC Strategic Research Priority Theme of "Resilience, Repair, and Replacement" and has the potential to impact on the health sector both in the short term and in the longer term. Short term benefits relate particularly to the link between unrepaired DNA single-strand breaks and neurodegeneration in cerebellar ataxias. For example, this project will address directly the hypothesis that inhibition of PARP1 activity is a putative therapeutic approach for treating neuropathologies associated with loss of single-strand break repair capacity. Although beyond the cope of the current application, since SSBs are the commonest DNA lesion arising in cells and are a cause of neurological dysfunction, it is possible that these lesions are also an etiological factor in degenerative disease in the normal (i.e. SSBR proficient) ageing population. This research might thus ultimately inform on environmental and life-style issues relating to healthy ageing in the normal population.
Publications
Adamowicz M
(2021)
XRCC1 protects transcription from toxic PARP1 activity during DNA base excision repair
in Nature Cell Biology
Breslin C
(2017)
The Rev1 interacting region (RIR) motif in the scaffold protein XRCC1 mediates a low-affinity interaction with polynucleotide kinase/phosphatase (PNKP) during DNA single-strand break repair.
in The Journal of biological chemistry
Caldecott K
(2022)
The threat of programmed DNA damage to neuronal genome integrity and plasticity
in Nature Genetics
Caldecott KW
(2022)
DNA single-strand break repair and human genetic disease.
in Trends in cell biology
Caldecott KW
(2020)
Mammalian DNA base excision repair: Dancing in the moonlight.
in DNA repair
Caldecott KW
(2019)
XRCC1 protein; Form and function.
in DNA repair
Cihlarova Z
(2022)
BRAT1 links Integrator and defective RNA processing with neurodegeneration.
in Nature communications
Demin AA
(2021)
XRCC1 prevents toxic PARP1 trapping during DNA base excision repair.
in Molecular cell
Hailstone R
(2023)
Biallelic PARP1 Mutations Associated with Childhood-Onset Neurodegeneration
Hanzlikova H
(2018)
The Importance of Poly(ADP-Ribose) Polymerase as a Sensor of Unligated Okazaki Fragments during DNA Replication.
in Molecular cell
Hanzlikova H
(2020)
Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair.
in Nature communications
Hanzlikova H
(2017)
Overlapping roles for PARP1 and PARP2 in the recruitment of endogenous XRCC1 and PNKP into oxidized chromatin.
in Nucleic acids research
Hoch NC
(2017)
XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
in Nature
Janiak FK
(2022)
Non-telecentric two-photon microscopy for 3D random access mesoscale imaging.
in Nature communications
Kalasova I
(2019)
Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ.
in Neurology. Genetics
Kalasova I
(2020)
Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair.
in Nucleic acids research
Komulainen E
(2021)
Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures.
in EMBO reports
Martinez-Macias MI
(2019)
FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I-induced DNA breakage and transcriptional stress.
in Life science alliance
Polo LM
(2019)
Efficient Single-Strand Break Repair Requires Binding to Both Poly(ADP-Ribose) and DNA by the Central BRCT Domain of XRCC1.
in Cell reports
Wu W
(2021)
Neuronal enhancers are hotspots for DNA single-strand break repair.
in Nature
Zagnoli-Vieira G
(2020)
Untangling trapped topoisomerases with tyrosyl-DNA phosphodiesterases.
in DNA repair
Zagnoli-Vieira G
(2018)
Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23)
in Neurology Genetics
Zeng Z
(2017)
Acylpeptide hydrolase is a component of the cellular response to DNA damage.
in DNA repair
Description | site specific SSBs in neurons |
Organisation | National Institutes of Health (NIH) |
Department | National Cancer Institute (NCI) |
Country | United States |
Sector | Public |
PI Contribution | We provided expertise and intellectual input in the conception, design, and interpretation of DNA repair aspects of study, resulting in myself being a co-corresponding author in a manuscript currently under review at Nature. |
Collaborator Contribution | Our collaborators (led by Andre Nussenzweig and Michael Ward) conceived, designed, and conducted deep sequencing approaches for the detection of site-specific SSBs in neurones. |
Impact | manuscript under revision at Nature journal |
Start Year | 2020 |