Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice

Abstract

DNA damage ͉ nucleotide excision ͉ base excision ͉ xeroderma pigmentosum ͉ Purkinje cells

The role of Cockayne Syndrome group B (CSB) protein in base excision repair and aging

“…Another comparative gene expression study established that CSB is involved in transcription of genes involved in chromatin maintenance and remodeling (Newman et al, 2006). CS cells display a stronger apoptotic response to DNA damaging agents than normal cells Laposa et al, 2007;Liu et al, 2006), which in part could explain why no cancer is seen in the patients. This CSB dependent apoptosis response seems independent of p53 Lu et al, 2001).…”

“…It is argued that the TCR deficiency of oxidative damage could be responsible for the progressive neurological disorders seen in CS patients (de Waard et al, 2003;Laposa et al, 2007;Osterod et al, 2002;Pastoriza-Gallego et al, 2007). This area of study has been filled with controversy, but one model proposes that the TCR of oxidative damage would be due to the arrest of RNA polymerases at oxidative DNA base lesions.…”

Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging

“…CSA and CSB cells are however different in their responses to oxidative damage, despite overlap in clinical symptoms (de Waard et al, 2004;D'Errico et al, 2007). The oxidative lesion 8-oxo-G does not appear to accumulate in CS autopsy material (Hayashi et al, 2005) despite the higher amounts of protein oxidation and lipid oxidation in the brains of CS patients (Hayashi et al, 2001) and crossing Cs-b mice with Ogg1 deficient mice did not enhance the neurological symptoms (Laposa et al, 2007b). Surprising is the absence of reported neurological or aging phenotypes among mouse strains lacking glycosylases which are the recognition and excision enzymes for BER that would be expected to show increased sensitivity to ROS (Friedberg et al, 1998), although many oxidative base damages are not transcription blocking lesions (Kathe et al, 2004).…”

“…Therefore loss of these functions should have little impact on differentiated brain tissue that is predominantly nondividing and heavily dependent on TCR. Crossing Cs-b mice with Xp-c mice, however, strongly enhanced the neurological symptoms showing that XPC is not without some relevance to neurological maintenance (Laposa et al, 2007b). Some evidence suggests that XPC is required for repair of oxidative damage that might be necessary in the brain (Kassam and Rainbow, 2007).…”

“…The neurodegenerative symptoms in mice are generally milder than in human and the cancer burden higher, especially for Cs (van der Horst et al, 1997;van der Horst et al, 2002;Laposa et al, 2007b) and Xpa De Vries, 1997;Tanaka et al, 2001). Variations due to strain backgrounds are also factors, especially regarding life-shortening versus cancer risk (Li et al, 2007;Partridge and Gems, 2007).…”