Stunted growth, impaired development of the nervous system, abnormal sensitivity to UV light and premature ageing are just some of the symptoms that young CS patients start to exhibit just a few months after birth or in the early years of their lives. In most cases, patients die in their teens or early adulthood.

“When I was doing my first postdoc in England, I had the opportunity to meet children who were suffering from this disease,” Maria Fousteri, beneficiary of the CHROMOREPAIR research grant, recalls. “This encounter really made me want to find out what happens and made me want to help these children.”

The molecular biology of the syndrome remains poorly understood. However, some 20 years ago, researchers did find out that CS sufferers have difficulty repairing lesions from UV light that are induced in genes, i.e. damage to actively transcribed DNA. “As a result, their cells will not be able to restore gene expression and will ultimately lack some proteins that are very important for the cells to operate,” explains Fousteri.

Wide-ranging impact

While CS is rather rare, DNA damage and deficiencies in repairing such damage are relevant to a range of human diseases, from neurodegenerative disorders to cancer. Improving our understanding of the underlying genome maintenance mechanisms, such as the transcription-coupled nucleotide excision repair (TC-NER) mechanism, which is affected in CS patients, will help researchers assess risks posed by environmental hazards and provide insight into the causes of ageing, age-related health problems and more.

Specifically, Fousteri looked into the role of chromatin remodelling in TC-NER that might be affected in CS. DNA is packaged tightly into chromatin – a complex of molecules – so that it fits in the cell. Chromatin plays a central role in the repair of DNA damage and controls gene expression and DNA replication, among other things.

Tight packaging of DNA into chromatin impedes access to DNA for repair purposes. In healthy people, the chromatin structure is therefore remodelled to allow access to the damage sites, allowing repair and DNA transcription (or copying) to continue. Failure to repair this damage and resulting prolonged interruption of transcription activity may lead to genomic instability or cell death. This, in turn, probably contributes to CS symptoms.

Similar but different

Through their research, Fousteri and colleagues in Rotterdam with whom she collaborated during CHROMOREPAIR characterised the functions of a novel gene, UVSSA, which plays an important role in the TC-NER mechanism – a process critical to restoring gene expression after damage.

People with mutations to this gene exhibit UV sensitivity, just like CS patients. But they do not have CS patients’ neurodegenerative problems, says Fousteri.

The team studied the importance of the protein produced by this gene – as well as the genes that carry mutations in CS sufferers – for the TC-NER mechanism. The researchers analysed how the results, i.e. very severe CS and the relatively mild UV-sensitive syndrome (UVSS), can be so different from one another, although the same mechanism, namely TC-NER, is compromised.

The findings from CHROMOREPAIR, as well as data gathered in the process, are the foundations for Fousteri’s work today.

The project gave her the opportunity to prove her mettle as an independent researcher, giving impetus to her career and ultimately leading to her election as research group leader at the Biomedical Sciences Research Center ‘Alexander Fleming’ in Greece. There she continues her research to the benefit of patients suffering from CS and other DNA damage-related disorders.