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Chromosome number abnormalities are a common cause of infertility in humans. The trend to have children at a later age has important implications for women due to age-related infertility, often caused by chromosome number abnormalities. The ?two hit? hypothesis proposes that the first hit is the lack of a ?crossover? which holds the two similar (?homologous?) chromosomes together. The second hit is related to the how well chromosomes are kept together until the cell divides ( spindle checkpoint ). We propose to use budding yeast as a model organism to find highly evolutionarily conserved genes that affect chromosome number abnormalities in gametes. Our preliminary data suggest that several factors, including temperature, affects how well chromosomes that have not received a crossover disjoin from each other. Interestingly, these genes also function in crossover formation. The genes that we identify in budding yeast will be analysed at the molecular and cellular level before we attempt to generate mouse models. We hope to identify genes that underlie age-related infertility in women in order to understand this phenomenon and to develop diagnostic test to prevent the condition.

Damage to our genetic material, DNA, occurs everyday and if left un-repaired can lead to cell death and/or cancer development. Our DNA can be damaged not only as a result of exposure to genotoxic chemicals or radiation but also indirectly, during normal cellular metabolism. For example, certain enzymes actually introduce breaks at specific locations in our DNA in certain cell types as a normal step during activation of our immune system. This allows the splicing together of distinct pieces of DNA to form new gene combinations to make specific antibodies. Several human genetic disorders exist that are defective in the normal response to DNA damage. One such disorder, Seckel syndrome, can be caused by a mutation in the ataxia telangiectasia and Rad3-related (ATR) gene. This gene creates a protein that functions as a key regulator of the normal response DNA damage. Seckel syndrome is characterised by profound growth retardation, skeletal abnormalities and a dramatically reduced head circumference which denotes a particular brain abnormality called ?microcephaly?. This suggests that the ATR protein plays some fundamental role during skeletal and brain development. What this role is has not been previously determined. This proposal aims to characterise how defective ATR impacts on these processes and results in such a severe condition as Seckel syndrome.

We aim to turn a novel quantum sensor based on a Bose-Einstein condensate (BEC) atomic probe into a scientific instrument. As we have recently demonstrated, a BEC microscope can image magnetic patterns and active electric current pathways in two-dimensional samples with ultra-high sensitivity (picotesla/nanoampere) and micrometre resolution. The main purpose of the project is to further develop and exploit the unique capabilities of BEC microscopy to make advances in the field of nanomaterials and their applications. Magnetic imaging allows for detecting active current flow rather than measuring conductivity which is the standard characterisation property in electrical testing. Imaging the active current flow enables the observation of functional responses in complex conductive samples, therefore, such an instrument is in high demand in materials science and a wide range of application fields. Until recently, no suitable magnetic imaging technology has been available to observe these functional responses, as existing technologies have been fundamentally limited by the trade-off between sensitivity and resolution. With this project we will demonstrate how BEC microscopy can deepen our understanding of the structure-property relationships in nanomaterials and accelerate the development of novel conductive materials such as transparent electrodes based on random networks of nanowires. We will also apply the BEC microscope to help new discoveries in bioengineering by investigating how cells respond to electrical stimulus on carbon nanotube scaffolds for example when directing the differentiation of stem cells into neural cells which could have huge implications in future therapies.

DNA is unstable and it can bear different types of lesions. We study breaks which affect both strands of DNA, the Double Strand Breaks (DSBs). DSBs can be repaired in an error free manner by copying the information from the sister chromatin using Homologous recombination. But they can also lead to deletions which can be either small if Non Homologous End Joining (NHEJ) is used, or larger if the ends are re-joined using the microhomology found in the two sides of the break, via Microhomology Mediated End Joining (MMEJ). Deletions signatures from these pathways have been found in cancer genomes. DNA is in the form of chromatin and chromatin is not linear, but it is folded in three dimensions and associates with different nuclear compartments which further specify chromatin characteristics. A DSB also leads to extensive remodelling of the chromatin structure around the break with histone exchange and alterations of histone modifications. Currently, it is unknown to what extend the epigenome is restored after DNA damage. Permanent genetic and epigenetic scars can alter gene expression profiles and are hallmark of cancer. If these scars occur in embryos or in stem cells, they can alter cell identity and the reprogramming potential. Our work together with work from other labs demonstrated that active chromatin is more prone to error-free repair and that compacted chromatin is more to MMEJ/NHEJ. Chromatin and 3D genome organization is cell type specific and dramatically changes during differentiation. In addition, stem cells bear a very unique chromatin feature which in called bivalency in which active and inactive chromatin marks exist together at the same nucleosome and decorates developmentally regulated promoters and protects them from DNA methylation observed in cancers. It is currently unknown: 1. Do DNA repair pathways adapt to changes in chromatin 3D genome organization to confer a cell type specificity in DNA repair fidelity? 2. Is the epigenome fully restored after DNA damage? In this proposal we will use mouse Embryonic Stem cells and study the spatial regulation of DNA repair fidelity and how this changes upon differentiation in different lineages . Then we will investigate the mechanisms controlling DNA repair fidelity at each chromatin state. Finally, we will ask whether the changes at the chromatin structure are fully restored after DNA damage and study the impact of genetic and epigenetic scars in stem cell identity. Our proposal will elucidate the complex relationship between genome and epigenome integrity and its link to mutagenesis and cell identify. Recently, there has been considerable effort in developing genome editing methods which are based on generation of DNA lesions by CRISP Cas nucleases used in this proposal. Therefore, our results will be very valuable for medical and research purposes as detailed understanding of genome editing effectiveness and particularly fidelity and precision in embryonic stages and how this altered in adult tissues, is of paramount importance for correcting disease mutations at stem cells which can then differentiated in the lab to the tissue which is affected by a disease.