Cockayne Syndrome

Fig.1 Continuous spectrum of severity in CS. (Laugel, 2013)

Overview of Cockayne Syndrome

Cockayne syndrome (CS) is a neurocutaneous disorder named in the 1950s after a dermatologist who practiced in the early decades of the 20th century. Cellular studies in the 1970s discovered that CS fibroblasts were sensitive to killing by ultraviolet (UV) light, ushering the subsequent avalanche of studies on the molecular characterization of this disorder. The UV sensitivity was shown to be associated with a failure of CS cells to recover RNA and DNA synthesis after UV damage. This property was used to demonstrate that there were two genes uniquely involved in the disease, named CSA and CSB (also ERCC8, ERCC6 respectively), and that there was overlap with another UV sensitive disease xeroderma pigmentosum (XP). The failure of RNA synthesis to recover after irradiation was found to correlate with loss of rapid excision repair subsequently discovered in actively transcribed genes (transcription-coupled repair, TCR). The arrest of RNA polymerase II (RNA-Pol II) at a damaged site is now recognized as the initiating signal for TCR. The failure of DNA synthesis to recover has been less well investigated and may be secondary to the impact of CS mutations on RNA transcription.

Regulating Factors of Cockayne Syndrome

CS is caused by recessive mutations in two genes, CSA (ERCC8) and CSB (ERCC6). CSB is a DNA-dependent ATPase of the SWI2/SNF2 family that binds to lesion-stalled RNA-Pol II and recruits pre-incision NER factors. CSA is a 44 kDa WD-repeat-containing scaffold protein that assembles in a Cullin4-DDB1-RING ubiquitin ligase complex, termed CRL4CSA. CSA determines the substrate specificity of the complex with CSB as one of its potential clients. CSA, like CSB, binds to lesion-stalled RNA-Pol II and is important for the recruitment of several factors including HMGN1, XAB2, TFIIS, and UVSSA. Mutations in the CSA gene are generally associated with moderate (type I) and mild (type III) forms of CS, while a mutation in the CSB gene covers the whole spectrum of CS phenotypes, including prenatal onset forms of CS (type II), and a severe variant termed COFS (Cerebro-oculo-facio-skeletal-syndrome) that is characterized by different dysmorphic facial features (microcephaly, small deep-set eyes, prominent nasal root, and large ear pinnae), severe nervous system abnormalities, and absence of the cachectic appearance typical of CS.

Fig. 2. Nuclear and mitochondrial functions of the RNA Pol II cofactors CSA, CSB, UVSSA, and USP7 that regulate the transcription of damaged DNA and facilitate enhanced repair of the transcribed strand. (Cleaver, 2013)

Treatment of Cockayne Syndrome

The complexity of CS likely precludes one single therapeutic option; each class of symptoms could require a different approach. As knowledge of the many facets of CS protein functions has developed, new options are emerging for potential treatments. If DNA damage from endogenous ROS plays a significant role in the pathology, the administration of antioxidants might be promising. Treatment of atm-deficient mice with the antioxidant CTMIO increased lifespan and reduced neurological symptoms. But evidence showed that some antioxidants damage DNA makes this less attractive. Other facets of CS may require different focused approaches. The deficiencies in IGF1 & growth hormone demonstrated in Cs-b mice could be supplemented by hormone replacement. Autophagy could be increased with lithium chloride or rapamycin to reverse the mitochondrial phenotype of Csb^m/m cells. Activation of autophagy by rapamycin has been successful in the treatment of a mouse model of TD-43 proteinopathies (frontotemporal lobar degeneration, amyotrophic lateral sclerosis) as well as several other neurodegenerative diseases.

Cockayne Syndrome Related Products at Creative Biolabs

If you are working on research on Cockayne syndrome, or you are looking for the assistance of neuro research, please feel free to contact us for more information.

References

1. Laugel, V. Cockayne syndrome: the expanding clinical and mutational spectrum. Mech Ageing Dev. 2013, 134(5-6): 161-70.
2. Cleaver, J. E.; et al. Conceptual developments in the causes of Cockayne syndrome. Mech Ageing Dev. 2013, 134(5-6): 284-90.