DNA Repair

DNA, the repository of genetic information for each of our cells, is a chemical entity that is subject to damage which if not repaired, can lead to mutations and disease1. As a result, cells have several mechanisms that are able to detect and repair the damage, whatever the cause.

Before allowing DNA to be duplicated, cells have checkpoint mechanisms to ensure that the DNA is intact and has been repaired properly. Inherited defects in the cellular checkpoint and repair machinery are known to cause a diverse array of genetic diseases, which not only have a deleterious impact on a multitude of the body’s organs but can also predispose individuals for developing cancer.

One such genetic disease is ataxia-telangiectasia (A-T), a multisystem, neurodegenerative disorder, which primarily presents with progressive degeneration of a specific part of the brain that controls balance and coordination, leaving affected individual wheelchair-bound before the age of 10 years old. Since the prevalence of A-T is 1: 300,000 live births, it has been given the designation of a rare disease. It is in the study of this and other rare diseases and the mutations in the genes which cause them that Professor Grant Stewart of the University of Birmingham’s Institute of Cancer and Genomic Sciences, finds his niche.

Rare Diseases

Professor Stewart’s work with rare diseases all stems from his work as a Ph.D student at the University of Birmingham under the supervision of Professor Malcolm Taylor, studying the genetics of A-T. He takes a step back from discussing his research to describe how this came about. In addition to neurodegeneration, Professor Stewart explains, individuals with A-T have problems with immunodeficiency and a predisposition for developing cancer; mainly leukaemia and lymphoma, but if they live long enough they can also develop solid tumours such as breast and brain cancers. The gene causing A-T is known as the ATM (ataxia-telangiectasia mutated) gene and is located on the long arm of chromosome 11. This gene controls the production of an enzyme which helps with regulating cell division following the occurence of DNA damage2.

A chromosomal spread using cells from an individual with an inherited deficiency in DNA replication/repair. The black arrows indicate spontaneously occurring chromosome gaps, breaks and fusions indicative of increased chromosomal instability.

ATM is activated or switched on when double-strand breaks occur in the cell’s DNA and it specifically functions to help repair this type of damage. Whilst DNA double-strand breaks can arise spontaneously in any cell type at any time, they can be induced in cells following exposure to radiotherapy, x-rays, naturally occurring radon and certain types of chemotherapy. Cells from individuals with A-T completely lack the ATM protein and therefore cannot properly sense and repair DNA double strand breaks. As a consequence, the treatment of individuals with A-T with chemo- or radiotherapy is highly toxic and can potentially kill the patient. However, this is not just about A-T though, as it turns out that the ATM gene is frequently mutated in many tumour types commonly found in the general population.

Mutations in the ATM gene causes cells to misrepair DNA damage and it is known that the accumulation of this misrepaired DNA damage helps to promote the transformation of normal cells into cancer cells. Therefore, even if you don’t have A-T, it is possible that a cell in a healthy person’s body might spontaneously acquire mutations in the ATM gene and it is this genetic event, which can push a normal cell onto the road of becoming a tumour cell.

The importance of studying ATM is that mutations in this gene not only contributes to the development of a tumour, but also determines how it responds to certain types of chemotherapy: often tumours with ATM mutations are more aggressive, do not respond well to chemotherapy and usually relapse following treatment. “So”, Professor Stewart says, “whilst we primarily study A-T to understand how loss of the ATM protein causes such a debilitating neurodegenerative disease and how it could potentially be treated, we can also apply what we have learned from studying A-T to help us treat tumours in the general population that have acquired ATM mutations.”

In addition to ATM, there are other DNA repair genes that function in the same pathway as ATM to sense and repair specific types of DNA damage, such as DNA double strand breaks. As with ATM, mutations in these other DNA repair proteins can also cause disease in humans which Professor Stewart also studies. For example, during his PhD, he discovered A-T can be caused by mutations in another DNA repair gene called MRE11A. The reason for these similarities is that the genes work together, resulting in similar clinical deficits in the absence of one or the other.

Professor Stewart’s lab is now keen to identify new genes that we do not know are associated with disease, now a possibility due to how cheap genome sequencing is. Rare genetic diseases are by their very name ‘rare’. However, since there are over 7000 different rare human diseases, of which 80% have a genetic basis, this means that approximately 1 in 17 people in the UK has a rare human disease. Unfortunately, most of these are children. Despite huge amounts of money being spent on researching human diseases, the majority of these rare diseases remain undiagnosed and as a consequence, do not have an effective treatment. The only way to change this is to study the disease at a cellular level.

Professor Stewart uses cells from patients with suspected a DNA repair deficiency syndrome, and studies how they react to DNA damage. This type of work is important for not only being able to provide a confirmed genetic diagnosis for the affected individual and their family but also when carrying out prenatal diagnoses and helping with genetic counselling. In addition, this diagnosis can be vital in situations when a patient may need chemo- or radiotherapy to treat a tumour as using the wrong type of treatment could kill the patient.

Once rare diseases are identified, often the same genes mutated in these patients are found to be mutated in sporadic cancers that develop in the general population. Consequently, the information that has been gathered from studying the rare genetic disorder and how the cells respond to specific types of DNA damage can help to determine the best therapeutic agents for treating these cancers.

Personalised Medicine

“Tumours are not the same” explains Prof Stewart, “even if you have two people have the same type of tumour, those tumours are not the same, genetically”. This means that how the tumour responds to treatment can be very different in different people, even people with the same tumour type. This is due to the genetic heterogeneity of cancer. Whilst tumours of the same type will often have a set of genes that are commonly mutated, there are many other genes that may be mutated in one tumour but not the other. It is often these genetic differences between tumours that can pivotal in determining the outcome of a tumour following treatment.

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Professor Stewart provides some insight into why chemotherapy does not always work, through an explanation of a process called ‘apoptosis’ or ‘programmed cell death’, which can be induced in a variety of ways including through damaging DNA. Normally, chemo- or radiotherapy is used to kill tumour cells by the DNA damage-inducing apoptosis, which requires the ATM protein along with another protein called TP53. If a tumour has a mutation in either the ATM or TP53 gene, the pathway of cell death is blocked i.e. apoptosis is prevented from occurring. As a result, the chemotherapy is often ineffective, which will allow the tumour to start growing once again. This highlights the importance of defining the genetics of tumour cells prior to treatment, understanding how individual DNA repair proteins normally function and knowing what the consequences are for a cell if these DNA repair proteins are mutated. This information can have a huge influence on whether a cancer patient lives or dies.

“Yes, it is based on genetic factors, and we are really moving in the last two decades from empirical treatment towards personalised treatment, meaning every category of tumours gets the appropriate treatment”. These are the words of Professor Stewart’s colleague, Tatjana Stankovic, a Professor in Cancer Genetics also at the Institute of Cancer and Genomic Sciences. Her group is taking scientific knowledge obtained from work like Stewart’s and using it to bridge the findings related to cancer biology in basic science, with possibilities of therapeutic implications and the way it can be implemented in the context of patients with cancer.

Synthetic Lethality

Professor Stankovic and her group focus on DNA damage response, and they are more interested in cancer cells with DNA damage response defect: since they are missing a particular damage response, they develop alternative pathways of survival that do not operate in normal cells. It follows that if therapeutics can inhibit the alternative pathway known as the dependency pathway or addiction, then tumour cells can be killed while sparing non-tumour cells. Simply put, they are looking for vulnerability in cancer cells with a DNA damage response defect with a view of tumour-specific killing.

Their specific disease model of choice is chronic lymphocytic leukaemia, a type of leukaemia in which DNA damage response defects are frequently present. The inability of cancer cell with a DNA repair defect to survive if the use of an alternative pathway is prohibited is called synthetic lethality. Using CRISPR screen, they can identify the mechanisms and pathways cancer cells use for survival and similarly look for means of pharmacological inhibition of these pathways. In fact, there are already several damage response inhibitors in clinical use and in clinical trials and the art is now learning in which patient settings they can successfully be applied. This is a task for translational scientists such as Professor Stankovic who attributes the discovery of synthetic lethality to basic scientists, but this knowledge now requires translation into patient care, something she has the expertise and knowledge to do.

Immunomodulation

There is now greater emphasis on targeted treatments due to the research done in that area in recent years. Another promising, new range of therapeutic interventions in some cancer tumour types is immunomodulation, a concept that Professor Stankovic explains for us: “Accumulation of unrepaired DNA damage can induce anti-tumour immunity if immune cells are capable. If not, there is a possibility they can be awakened if you like, to recognise this accumulated damage, and also accumulated damage creates what we call neoantigens which are proteins expressed in tumour cells but not in normal cells and there is a potential to induce immunity to recognise this.”

Birmingham at the Forefront

What draws Professor Stankovic to this cutting-edge research? As a trained clinician, she has been involved in treatment of patients with leukaemias and lymphomas in a paediatric setting.  “I was always puzzled by heterogeneity of (the) clinical response because not every tumour responded the same way.” The reasons for this led her to acknowledging the significance of the genetic makeup of tumour cells, allowing her to recognise the genetic reasons for heterogeneity in therapeutic response and ultimately the DNA damage response which is behind it all.

She, like Professor Stewart, thinks that there is a cluster of expertise at Birmingham which gives them the unique opportunity to excel in this area. They have ambitious basic scientists who carry out DNA research, and they also have physicians interested in translational medicine in oncology in paediatric and adult settings. This goes alongside a fantastic clinical trial centre, giving them the distinctive ability to combine basic research with clinical necessity in clinical trials.

Birmingham is also well situated in an area with ethnic diversity and instances of rare diseases, placing at their door opportunities for further research with ramifications for identifying new pathways and new therapeutics.

Only the Beginning

There is still work to be done, but Professor Stankovic is very optimistic, admitting that there is some disappointment as we do not yet have perfect stratification of cancer patients which is key to progress. While we now have a range of different agents, we have on the other side a vast heterogeneity of tumours with a need to marry the two, finding the categories of patients that respond to specific treatments and finding other treatments for those that do not respond.

1. Nature – DNA Damage & Repair: Mechanisms for Maintaining DNA Integrity (2008)

2. National Organization for Rare Dieseases – Ataxia Telangiectasia (2007)

Professor of Cancer Genetics

Professor Grant Stewart is Professor of Cancer Genetics in the Institute of Cancer and Genetic Sciences. He is also joint theme lead of Cancer Genomics research theme for the Cancer Research UK Birmingham Centre.

Grant’s profile

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Professor in Cancer Genetics

Professor Tatjana Stankovic has published over 90 research papers in high impact scientific journals as well as reviews in the fields of cancer genetics and DNA damage response.

Tatjana’s profile

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