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Blizard Institute - Faculty of Medicine and Dentistry

Q&A: How a DNA repair gene can cause bone marrow failure

Dr Hemanth Tummala and colleagues from the Blizard Institute had research published this week in the journal PNAS, which finds a new role for a gene in DNA repair.

Primarily funded by the Medical Research Council and Bloodwise charity, the researchers studied children with inherited bone marrow failure (IBMF) to find mutations that might be causing their disease.

In this Q&A, Dr Tummala explains the significance of the research and how it might lead to new treatments for cancer.


What is new about the study?

We have been studying children who have inherited a severe life-threatening condition that affects the bone marrow leading to deficiency in mature blood cells. Using whole exome sequencing, we identified mutations in the DNA repair gene ERCC6L2 in four different families.

We discovered that patient cells are prone to DNA damage due to presence of transcriptional by-products called DNA-RNA hybrid structures (R-loops). Intriguingly, the increase of R loops in patient cells appears to impact transcription and DNA repair efficiency. Based on our genetic and molecular findings, we believe the bone marrow failure in these patients is principally an inherited transcription deficiency.

Is there anything surprising about the results?

Yes, our study reveals a new role for ERCC6L2 in transcription associated DNA repair. This pathway is often dysregulated in many human cancers and neurodegenerative conditions such as Cockayne syndrome.

Why is the study important?

DNA replication and transcription are two basic cellular processes that occur on the same DNA template to decide cell fate. Conflicts between these two processes cause DNA damage/genome instability and it is important to identify key factors involved in these functions.

In this study we reveal that ERCC6L2 is a component of the transcription complex and it minimises transcription-associated genome instability by resolving R-loops. Numerous other investigations indicated that the transcription complex interacts with other proteins involved in DNA repair, but current evidence about the details of these interactions is lacking.

We have established that ERCC6L2 primarily interacts with a DNA repair protein ‘DNA-PK’ and remarkably tailors specific needs for transcription associated DNA repair process.

Lastly, we noticed that the molecular function of ERCC6L2 is similar to CSB (ERCC6) which is mutated in most cases of Cockayne syndrome. To date neither bone marrow failure or cancer predisposition has been reported in cases with Cockayne syndrome, warranting further investigation to dissect the precise molecular function in more detail.

What are the wider implications?

DNA damage and subsequent repair have many important consequences for human health. Cancer predisposing syndromes such as bone marrow failure have been associated with congenital deficiencies in DNA repair (e.g. Fanconi anaemia).

Moreover, cancer treatment is often based upon damaging DNA or inhibiting DNA repair in the diseased tissue. Therefore, we believe it is essential to discover new factors that are involved in the interface between transcription and DNA repair. We hope the discovery of ERCC6L2 at this interface will open new therapeutic opportunities in targeting cancer cells with specific DNA damaging agents.

This discovery will immediately impact on the families themselves, in that we have provided a definitive genetic diagnosis that will enable better family planning. It shows the power of modern gene sequencing techniques to identify the underlying cause of a life threatening disease. By defining the precise primary defect, this study enables appropriate patient management and genetic counselling of family members.


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