Chapman Group: Homologous recombination in genome maintenance and cancer prevention

About the Research 

Genomic instability (GI) is a hallmark of cancer that plays a central role in its initiation and development. GI can arise as a result of germline or somatic mutations that compromise a cell’s ability to accurately sense, signal or repair DNA damage. GI can also arise as a consequence of errors in chromosome segregation during mitosis, or when chromosome breakage events lead to chromosome rearrangements, and/or gains and losses to daughter cells following cell division. These catastrophic events are not only linked to tumour initiation, they also play a central role in cancers ability to evolve and acquire new aggressive traits, such as the ability to metastasize, or become resistant to anti-cancer therapies. However, in some specialised cell types, genome rearrangements must occur as programmed, highly orchestrated events, where they function to bring about genetic diversity.

Research in the Chapman laboratory aims to better understand the biological pathways that ensure DNA damage is accurately repaired, and their interplay with error-prone DNA end-joining mechanism that support programmed genome diversification as a physiological process. The laboratory has a long-standing interest in the BRCA1 tumour suppressor pathway, which coordinates the accurate repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) with an active suppression of mutagenic DNA end-joining mechanisms, such as non-homologous end joining (NHEJ)^1–3. Complementary arms of our laboratory’s research investigate the physiological purpose of the same mutagenic DSB repair pathways, such as in the adaptive immune system where NHEJ is essential^1,4,5. We have also become interested in the mechanistic action and regulation of recently discovered mitotic DSB repair pathways, whose action on unresolved DNA breaks, under-replicated DNA and/or joint DNA molecule products of recombination pathways ensures for timely DNA damage resolution before chromosome segregation.

Incompletely replicated regions of the genome pose an important challenge for the stability of mammalian genomes. Late replicating, structurally complex and/or repeat-rich regions of mammalian genomes underpin the biology of common fragile sites (CFS), heritable regions on mammalian chromosomes that show an increased propensity for breakage and pathological rearrangement under conditions of disrupted or stressed DNA replication, leading to devastating genomic instability. Recent genome-wide CRISPR-Cas9 screening experiments in our laboratory have highlighted CFSs as being particular problematic in cells deficient in the homologous recombination (HR) DNA repair pathway due to loss-of-function mutations affecting the BRCA1 tumour suppressor gene. Interestingly, however, the molecular basis of CFS resolution and HR-dependent DSB repair by BRCA1 occurs via mechanisms that can be genetically and functionally uncoupled. The goal of this project is to build on these results to investigate the molecular interplay between cellular mechanisms that act to enable completion of DNA replication through structurally complex regions within mammalian genomes, and the BRCA1-dependent DNA repair mechanisms that act on under-replicated DNA structures when they arise, to ensure for their timely resolution before cell division. This will involve a combination of molecular cell biology, molecular genetics and biochemical approaches. The project will also involve genomics and cutting-edge genome editing technologies, such as targeted and screening applications of the CRISPR-Cas9 system and newly developed next-generation sequencing-based DNA damage mapping technologies. Where appropriate (optional), in vivo approaches can be used to investigate and define the physiological purpose of this biology, and the tissue and context-specific consequences of its inactivation or dysfunction in human disease and cancer.

Training Opportunities 

Interdisciplinary by design, DPhil projects will utilise a broad range of cutting-edge molecular and genetic technologies, and will foster interactions with multiple labs in the WIMM. Experimental approaches in the lab include advanced molecular biology, quantitative proteomics, quantitative and super-resolution imaging, CRISPR-Cas9 genome editing, structural biology and in vivo experimental approaches. The laboratory also utilises genome-wide screening approaches, and is developing methods to analyse the repair of endogenous DNA breaks on a genome scale. Training opportunities at the WIMM also exist to develop expertise in basic and advanced bioinformatics.

Students will be enrolled on the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence, and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

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