Berneburg M, Lowe J E, Nardo T, Araújo S, Fousteri M I, Green M H, Krutmann J, Wood R D, Stefanini M, Lehmann A R
MRC Cell Mutation Unit, Sussex University, Falmer, Brighton BN1 9RR.
EMBO J. 2000 Mar 1;19(5):1157-66. doi: 10.1093/emboj/19.5.1157.
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.
核苷酸切除修复（NER）通过一个严格调控的多蛋白过程去除DNA损伤。NER缺陷会导致三种不同的人类疾病，即着色性干皮病（XP）、毛发硫营养不良（TTD）和科凯恩综合征（CS）。两例具有XP和CS联合特征的病例被归入XP-D互补组。尽管这些细胞对紫外线极度敏感，但在受到紫外线损伤时，它们切割DNA的效率似乎与正常细胞一样高。然而，这些切割与修复过程的其他部分脱节。使用无细胞提取物，我们在损伤附近未能检测到任何切割活性。当将经辐射的质粒导入未受辐射的XP-D/CS细胞时，异位引入的损伤会引发未受损基因组DNA的断裂诱导。因此，XP-D/CS细胞对紫外线损伤的感知具有独特的反应，这导致在远离损伤的位点将断裂引入DNA。我们认为正是这些假性断裂导致了这些细胞对紫外线的极度敏感性。
