DNA repair disorders

DNA repair disorders are rare genetic disorders in which there is a decreased ability to repair DNA damage. DNA repair disorders display a wide spectrum of developmental and degenerative nervous system abnormalities, varying from microcephaly (small brain), brain tumors, and premature degeneration. The symptoms strongly depend on which DNA repair pathway is affected. Nervous systems abnormalities occur in patients with deficiencies in the nucleotide excision repair (NER), a major DNA repair pathway known for its essential role in the repair of DNA lesions caused by ultraviolet (UV) light. NER-deficiency disorders range from UV-sensitivity disorders to the neurodevelopmental and accelerated aging conditions trichothiodystrophy (TTD), Cockayne syndrome (CS) and cerebro-oculo-facio-skeletal syndrome (COFS).

The NER pathway removes bulky helix-distorting DNA lesions by excising a 30-nucleotide fragment containing the lesion followed by gap-filling DNA synthesis and ligation. The NER pathway involves more than 30 factors, and consists of two main subpathways, global genome NER (GG-NER) and transcription-coupled NER (TC-NER), that differ in the damage recognition step. The heterogeneity of NER-deficiency syndromes at least in part can be explained by the large variety of NER factor and the presence of two subpathways. Grossly, nervous system abnormalities are associated with mutations in upstream TC-NER factors or in downstream NER factors that are involved in both TC-NER and GG-NER. Further heterogeneity in clinical symptoms may follow from defects in non-NER activities of NER factors. The preclinical research at the ENCORE expertise center focusses on a better understanding of the mechanisms underlying nervous system abnormalities in NER syndromes, in particular neurodegenerative abnormalities associated with Cockayne syndrome and Xeroderma Pigmentosa.

Preclinical research at the Erasmus MC on DNA repair is performed at the department of Molecular Genetics (focusing on the mechanism of DNA repair) and at the department of Neuroscience (focusing on the impact of impaired DNA repair on brain function).

Better understanding of DNA repair mechanisms.

We aim to understand the molecular mechanism and regulation of the DNA repair pathway Nucleotide Excision Repair and its impact on human health (also visit www.vermeulenlab.com). This important DNA repair process protects organisms against DNA damage-induced carcinogenesis (cancer development) and premature ageing. We use multidisciplinary research approaches to improve our understanding of its molecular mechanism, including (1) molecular genetic analysis, (2) biochemical and cell biological examinations, (3) up to the level of intact organisms.

This research also includes research-based molecular and functional analysis on cells derived from patients with inherited defects in DNA repair processes, offered to us from clinicians and researchers around the world. This service is currently coordinated by Dr. Arjan F. Theil and includes next to genetic analysis also functional DNA repair studies. Click here for more information about the service.

NER defects causes brain abnormalities.

To obtain a better understanding in the relationship between deficiencies in specific NER factors and nervous system abnormalities, we systematically examined nervous system abnormalities in a series of NER mutant mice that reliably recapitulate the repair defect and UV-sensitivity of corresponding NER syndromes. The mice develop a range of nervous system abnormalities that in part reproduce symptoms found in human syndromes. For instance, TCR–deficient Csa-/- and Csb-/- mice that are deficient in TC-NER develop subtle abnormalities in the white matter, and represent a potential mouse models for studying white matter abnormalities in Cockayne syndrome. Instead, mice deficient for the NER nucleases XPF/ERCC1 or XPG that operate in both GG-NER and TC-NER develop an accelerated aging phenotype with progressive neurodegenerative changes. These mice model severe forms of Cockayne syndrome. Studies with global mutants are complemented with neuron-specific mouse models. Refined neuropathological and biochemical analyses will provide further insights in the mechanisms underlying the diversity of abnormalities in NER-deficiency syndromes.

Towards treatments of NER-syndromes
The XPF/ERCC1 and XPG deficient mice that develop severe progressive degenerative phenotypes, proved to be efficient mouse models for testing therapeutic interventions. A major finding, so far, is that dietary restriction has a large beneficial effect in XPF/ERCC1 and XPG mice, prolonging their life span and reducing neurological deficits (Vermeij et al., Nature, 2016). These data indicate that dietary interventions may be beneficial for patients with NER deficiency syndromes. We are continuing dietary, pharmacological and genetic interventional studies to uncover the mechanisms and pathways underlying the protective effect of dietary restriction.

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Kuo M.E. & Theil A.F. et. al. (2019). Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails. Am J Hum Genet. pii: S0002-9297 Pubmed

Theil A.F. & Botta E. et. al. (2019) Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype. Am J Hum Genet. 105:434-440 Pubmed

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Marteijn JA, Hoeijmakers JH, Vermeulen W (2015) Check, Check …Triple Check: Multi-Step DNA Lesion Identification by Nucleotide Excision Repair. Mol Cell 59:885-6 Pubmed

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Borgesius N.Z. et.al. (2011) Accelerated age-related cognitive decline and neurodegeneration, caused by deficient DNA repair. J Neurosci. 31(35), 12543-53 Pubmed

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