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 regulated multiprotein process. Defects in NER result in three different human disorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS). Two cases with the combined features of XP and CS have bee...

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Bibliographic Details
Published in:The EMBO journal 2000-03, Vol.19 (5), p.1157-1166
Main Authors: Berneburg, Mark, Lowe, Jillian E., Nardo, Tiziana, Araújo, Sofia, Fousteri, Maria I., Green, Michael H.L., Krutmann, Jean, Wood, Richard D., Stefanini, Miria, Lehmann, Alan R.
Format: Article
Language:English
Subjects:
Base Pairing
Cells, Cultured
Cockayne syndrome
Cockayne Syndrome - genetics
Deoxyribonucleic acid
DNA
DNA breaks
DNA Damage - radiation effects
DNA Repair
Humans
nucleotide excision repair
trichothiodystrophy
Ultraviolet Rays
UV light
xeroderma pigmentosum
Xeroderma Pigmentosum - genetics
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Summary:Nucleotide excision repair (NER) removes damage from DNA in a tightly regulated multiprotein process. Defects in NER result in three different human disorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS). Two cases with the combined features of XP and CS have been assigned to the XP‐D complementation group. Despite their extreme UV sensitivity, these cells appeared to incise their DNA as efficiently as normal cells in response to UV damage. These incisions were, however, uncoupled from 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 irradiated plasmids were introduced into unirradiated XP‐D/CS cells, the ectopically introduced damage triggered the induction of breaks in the undamaged genomic DNA. XP‐D/CS cells thus have a unique response to sensing UV damage, which results in the introduction of breaks into the DNA at sites distant from the damage. We propose that it is these spurious breaks that are responsible for the extreme UV sensitivity of these cells.
ISSN:0261-4189
1460-2075
DOI:10.1093/emboj/19.5.1157