UV damage causes uncontrolled DNA breakage in cells from patients with combined features of XP-D and Cockayne syndrome

Nucleotide excision repair (NER) removes damage from DNA in a tightly regul ated multiprotein process. Defects in NER result in three different human d isorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayn e syndrome (CS), Two cases with the combined features of XP and CS have bee n assigned to the XP-D complementation group. Despite their extreme UV sens itivity, these cells appeared to incise their DNA as efficiently as normal cells in response to UV damage. These incisions were, however, uncoupled fr om the rest of the repair process. Using cell-free extracts? we were unable to detect any incision activity in the neighbourhood of the damage. When i rradiated plasmids were introduced into unirradiated XP-D/CS cells, the ect opically introduced damage triggered the induction of breaks in the undamag ed genomic DNA, XP-D/CS cells thus have a unique response to sensing UV dam age, which results in the introduction of breaks into the DNA at sites dist ant from the damage,We propose that it is these spurious breaks that are re sponsible for the extreme UV sensitivity of these cells.