Genomic integrity: protecting dividing DNA

11 November 2016

Dr Chris Kok-Lung Chan (2003 Croucher Scholar; 2007 Croucher Fellow) aspired to be a scientist from childhood, yet his economic circumstances meant that this would be difficult to achieve. Since then, he has completed his DPhil and made a discovery which has altered how the scientific community views chromosome disjunction. Today he is based in Sussex, England, where he is the Group Leader of the MRC Genome Damage and Stability Centre, which is currently exploring the importance of maintaining genome integrity, particularly focusing on the interplay between DNA replication and chromosome segregation in mitosis.

Genomic integrity is the continuous preservation of the genetic elements in an organism’s cells, and is lost when mutations in DNA sequences are not corrected, or when broken DNA sequences are not precisely fused back together. 

These initial problems can be caused by external factors, as DNA faces almost constant threat from exogenous forces, including UV light, radiation, chemicals and free radicals. These forces damage DNA by causing both direct mutations which can alter DNA sequences, or by physically breaking DNA, causing damage to genes and the components involved in regulation. 

Cells do have systems which can correct mutations and fuse breaks in DNA, however if these systems fail, problems with genome integrity arise. This can also occur when cells fail to copy chromosomes precisely, or when they fail to distribute each copy to offspring cells during the subsequent chromosome segregation process.

The loss of genome integrity can lead to the development of cancerous cells. Due to the nature of DNA as a double helix, its replication leads to intertwining between the duplicated copies. Complications can also arise if DNA replication is not fully completed, both situations will lead to the formation of so-called sister-chromatid bridging. 

Moreover, sister-chromatid bridging can also arise when recombination structures accumulate, physically entangling sister DNA molecules. It is extremely dangerous if cells fail to disentangle any of the DNA bridges, which can impede accurate chromosome separation during mitosis, therefore threatening genome integrity. Failure to resolve and separate sister-chromatid bridges can lead to chromosome breakage and then to chromosomal abnormalities, which prompts the development of cancerous cells.

Chan’s research focuses on understanding the different causes of intertwining DNA structures, as well as how they are subsequently separated, both before and during the process of cellular mitosis. 

His team has discovered a number of proteins within human cultured cells that either influence the formation of sister-chromatid bridging or aid in the resolution of this by separating the sister-chromatid bridges. Potentially all of these proteins are also involved in human inherited disorders which exhibit cancer predisposition. 

Chan made use of various approaches, including CRISPR technology, to remove genes of interest in human immortalised diploid cells and in cancer cells. Making use of high precision and super-resolution imaging, as well as advanced cytogenetic techniques, Chan and his team were able to investigate the alteration of chromosome structures in fixed cells and the chromosome segregation process in live cells. This research will hopefully reveal how the cancer genome develops and subsequently evolves.

Cancer cells have an abnormally high replication rate, and the stress of this can induce the formation of sister-chromatid bridging. These pathways can be targeted in a way which would reduce the growth rate of cancer cells without affecting the replication of normal cells. 

A long-term aim of the research would be to develop a targeting therapy aimed at cancers which are under high replication stress, as well as investigating and understanding the fundamental causes of chromosome instability. 

Chan’s lab has recently started a project with the Sussex Drug Discovery Centre in an attempt to identify small molecules which target one of the sister-chromatid bridge’s binding proteins.

Chan has an interest in photography, which complements his studies in cell biology and microscopy, and this interest has helped him visualise the organisation and distribution of chromosomes within DNA, as well as how they are distributed into offspring cells in real time. 

While his research explores fundamental science, the outcome could potentially provide a much more effective and gentle treatment for cancer patients. In the future, he dreams of creating a world-class team focusing on the interplay between the termination of DNA replication and chromosome segregation. In addition to this, he would like to improve and advance current imaging technologies to allow the majority of laboratories in the world easy access to high- or super-resolution imaging techniques.

Oxford

Despite long since being interested in science and receiving a conditional offer from Oxford University to study genome stability as part of his PhD, Chan did not expect he would be able to pursue scientific research overseas, as he came from a single-parent, low-income family which could not support such endeavours. 

A friend suggested that he contact the Croucher Foundation, who offered a full scholarship to pursue his research in Oxford. Chan has stressed the importance of this funding and its benefits to scientists globally from backgrounds similar to his. 

He said, “I feel very fortunate, having obtained [the Croucher Foundation] scholarship and later fellowship, which has changed my whole career. Their support has lead to many of my scientific discoveries, which in turn enabled me to obtain the prestigious Sir Henry Dale Fellowship, which has allowed me to establish my own research team in the UK. Their generosity has a great impact on researchers like me, allowing us to pursue our scientific dreams.” 

While he acknowledges that not all charities consider the background of students, Chan hopes that they will provide funding to students from marginalised socioeconomic backgrounds who are excelling in their studies, as these students often have little financial support from their families, and may find it more difficult to establish their research on their own.

Chan also appreciated the environments of Oxford and Sussex, “I really enjoy studying and working in the UK, where the creative culture opens up my mind and facilitates lots of my research thinking. At the moment, I think the UK is still the most suitable place for my research because of all the world-class technology, collaborations with leading scientists and funding supports.” In the future, Chan hopes to use his experience and knowledge to help the next generation of science students in Hong Kong, helping them go on to become world-class scientists.

Ultrafine DNA Bridges

It was during his DPhil at the University of Oxford that Chan not only discovered but also proved the existence of ultrafine DNA bridges in human mitotic cells. Previously, it was believed that sister chromatids had to be separated, with any DNA linkage destroyed, before the onset of chromosome disjunction. 

However, after being drawn in by the structures of chromosomes during the different phases of mitosis, Chan decided to do more careful cellular staining and imaging, and discovered ultrafine DNA bridges, which proved that this was not the case. He describes his finding as, “a big surprise to the field. It also suggests that the many things we have learnt from colleagues or universities might not be correct, and that’s why we need to keep putting more effort into finding out the truth.”

Establishing his own research group was challenging, but ultimately rewarding, as this opportunity provided Chan with comprehensive training, teaching him how to form his own research questions, establish a laboratory and incorporate new technology to tackle the questions. It has also provided him with the opportunity to teach young scientists. Chan’s discovery of ultrafine DNA bridges has opened up a new research direction within his field, creating many questions for his research team to answer.

Dr Chris Kok-Lung Chan was awarded a first-class honours B.Sc in Biotechnology from the University of Hong Kong (HKU), where he remained for his M.Phil in Pathology. In 2003, he won the Croucher Scholarship and Overseas Research Scholarship (ORS), allowing him to attend the University of Oxford for his D.Phil in Molecular Medicine. He continued to study at Oxford and was a Croucher Fellow in 2007, as he began his research into chromosome segregation. In 2014, the Wellcome Trust and the Royal Society awarded him the Sir Henry Dale Fellowship, allowing him to start his own research group in the MRC Genome Damage and Stability Centre in Sussex, England. Chan remains in Sussex, investigating the results of a loss of genomic integrity and cancer genome evolution.

To view Chan’s personal Croucher profile, please click here.