Honors & Awards
Fellow Award, Leukemia and Lymphoma Society (July 2016 - June 2019)
Doctor of Philosophy, University of Cambridge (2015)
Master of Arts (Cantab), University of Cambridge (2014)
Bachelor of Arts, University of Cambridge (2010)
Karlene Cimprich, Postdoctoral Faculty Sponsor
Current Research and Scholarly Interests
Investigating the role of R-loops in genome stability and human disease
- Faulty replication can sting NATURE 2018; 557 (7703): 34–35
Targeting Functional Noncoding RNAs.
Methods in molecular biology (Clifton, N.J.)
2017; 1565: 151-160
Noncoding RNAs have essential biochemical functions in different areas of cellular metabolism, including protein synthesis, RNA splicing, protein secretion, and DNA replication. We have successfully used Morpholino antisense oligonucleotides for the functional inactivation of small noncoding RNAs required for DNA replication (Y RNAs in vertebrates and stem-bulge RNAs in nematodes). Here we discuss specific issues of targeting functional noncoding RNAs for inactivation by Morpholino antisense oligonucleotides. We present protocols for the design, preparation, and efficacy controls of Morpholino antisense oligonucleotides, as well as brief descriptions for their delivery into vertebrate and nematode embryos.
View details for DOI 10.1007/978-1-4939-6817-6_13
View details for PubMedID 28364241
Structural and functional analysis of four non-coding Y RNAs from Chinese hamster cells: identification, molecular dynamics simulations and DNA replication initiation assays
BMC Molecular Biology
View details for DOI 10.1186/s12867-015-0053-5
Co-transcriptional R-loops are the main cause of estrogen-induced DNA damage
View details for DOI 10.7554/eLife.17548
Non-coding stem-bulge RNAs are required for cell proliferation and embryonic development in C-elegans
JOURNAL OF CELL SCIENCE
2015; 128 (11): 2118-2129
Stem bulge RNAs (sbRNAs) are a family of small non-coding, stem-loop RNAs present in C. elegans and other nematodes, the function of which is unknown. Here, we report the first functional characterisation of nematode sbRNAs. We demonstrate that sbRNAs from a range of nematode species are able to reconstitute the initiation of chromosomal DNA replication in the presence of replication proteins in vitro, and that conserved nucleotide sequence motifs are essential for this function. By functionally inactivating sbRNAs with antisense morpholino oligonucleotides we show that sbRNAs are required for S phase progression, early embryonic development and viability of C. elegans in vivo. Thus, we demonstrate a novel and essential role for sbRNAs during the early development of C. elegans. sbRNAs show limited nucleotide sequence homology to vertebrate Y RNAs, which are also essential for the initiation of DNA replication. Our results therefore establish that the essential function of small non-coding stem-loop RNAs during DNA replication extends beyond vertebrates.
View details for DOI 10.1242/jcs.166744
View details for Web of Science ID 000355559600011
View details for PubMedID 25908866
Functional roles of non-coding Y RNAs.
The international journal of biochemistry & cell biology
Non-coding RNAs are involved in a multitude of cellular processes but the biochemical function of many small non-coding RNAs remains unclear. The family of small non-coding Y RNAs is conserved in vertebrates and related RNAs are present in some prokaryotic species. Y RNAs are also homologous to the newly identified family of non-coding stem-bulge RNAs (sbRNAs) in nematodes, for which potential physiological functions are only now emerging. Y RNAs are essential for the initiation of chromosomal DNA replication in vertebrates and, when bound to the Ro60 protein, they are involved in RNA stability and cellular responses to stress in several eukaryotic and prokaryotic species. Additionally, short fragments of Y RNAs have recently been identified as abundant components in the blood and tissues of humans and other mammals, with potential diagnostic value. While the number of functional roles of Y RNAs is growing, it is becoming increasingly clear that the conserved structural domains of Y RNAs are essential for distinct cellular functions. Here, we review the biochemical functions associated with these structural RNA domains, as well as the functional conservation of Y RNAs in different species. The existing biochemical and structural evidence supports a domain model for these small non-coding RNAs that has direct implications for modular evolution of functional non-coding RNAs.
View details for DOI 10.1016/j.biocel.2015.07.003
View details for PubMedID 26159929
Nucleotide contributions to the structural integrity and DNA replication initiation activity of noncoding y RNA
2014; 53 (37): 5848-5863
View details for DOI 10.1021/bi500470b
CXCL12/CXCR4 Blockade Induces Multimodal Antitumor Effects That Prolong Survival in an Immunocompetent Mouse Model of Ovarian Cancer
2011; 71 (16): 5522-5534
The chemokine CXCL12 and its receptor CXCR4 are expressed widely in human cancers, including ovarian cancer, in which they are associated with disease progression at the levels of tumor cell proliferation, invasion, and angiogenesis. Here, we used an immunocompetent mouse model of intraperitoneal papillary epithelial ovarian cancer to show that modulation of the CXCL12/CXCR4 axis in ovarian cancer has multimodal effects on tumor pathogenesis associated with induction of antitumor immunity. siRNA-mediated knockdown of CXCL12 in BR5-1 cells that constitutively express CXCL12 and CXCR4 reduced cell proliferation in vitro, and tumor growth in vivo. Similarly, treatment of BR5-1-derived tumors with AMD3100, a selective CXCR4 antagonist, resulted in increased tumor apoptosis and necrosis, reduction in intraperitoneal dissemination, and selective reduction of intratumoral FoxP3(+) regulatory T cells (Treg). Compared with controls, CXCR4 blockade greatly increased T-cell-mediated antitumor immune responses, conferring a significant survival advantage to AMD3100-treated mice. In addition, the selective effect of CXCR4 antagonism on intratumoral Tregs was associated with both higher CXCR4 expression and increased chemotactic responses to CXCL12, a finding that was also confirmed in a melanoma model. Together, our findings reinforce the concept of a critical role for the CXCL12/CXCR4 axis in ovarian cancer pathogenesis, and they offer a definitive preclinical validation of CXCR4 as a therapeutic target in this disease.
View details for DOI 10.1158/0008-5472.CAN-10-3143
View details for Web of Science ID 000293831500018
View details for PubMedID 21742774