View PDF Version - RePub - Erasmus Universiteit Rotterdam
View PDF Version - RePub - Erasmus Universiteit Rotterdam
View PDF Version - RePub - Erasmus Universiteit Rotterdam
Create successful ePaper yourself
Turn your PDF publications into a flip-book with our unique Google optimized e-Paper software.
section, the phenotype of several of the NER-deficient mice is described, paying<br />
special attention to the role of endogenous DNA damage in the onset of some of the<br />
pathologic symptoms.<br />
ERCCl, premature aging and the stress response<br />
The ERCCI gene was the first human NER gene to be isolated via an NERdeficient<br />
Chinese hamster cell mutant as recipient for transfection cloning [31]. In<br />
contTast to other human NER genes cloned following the same strategy, subsequent<br />
studies excluded that ERCCI is involved in any known complementation group of<br />
the three human NER syndromes. This suggests that mutations in this gene are<br />
either very rare, lethal or induce an unexpected phenotype. The EReC I protein<br />
complexes with the XPF product and the resulting heterodimer has a stmcturespecific<br />
endonuclease activity incising the 3'-extending single strand at a double<br />
strand to single strand transition in DNA [32]. In the NER reaction mechanism this<br />
corresponds with the 5' incision of the damaged strand. In addition to NER, the<br />
ERCC lIXPF complex has a function in a mitotic recombination process that<br />
presumably is responsible for repair of intrastrand crosslinks. Chinese hamster<br />
ERCCI and ERCC4 (XPF) mutants are uniquely hypersensitive to DNA<br />
crosslinking agents such as mitomycin C (MMC) [33] and ERCCI-deficient mouse<br />
embryonic stern (ES) cells cany a defect in gene targeting by homologous<br />
recombination when the targeting constmct harbors heterologous ends (G. Weed a,<br />
unpublished observation). Similarly, MEFs isolated from ERCCI knockout mice<br />
Table II. Presumed or established involvement of NER proteins in diverse cellular processes<br />
NER compollell!<br />
TFI!I-I, CSB, CSA<br />
eSB, CSA, XPG (TfllH)<br />
[{]lA, PCNA, DNA poJymerases, ligase I<br />
RAD23a!b<br />
ERCCIIXPF<br />
Process<br />
Basal Transcription, Cell Cycle Regulation<br />
l3ase Excision Repair<br />
Replication<br />
Ubiquitination<br />
Cross Link Repair! Mitotic Recombination<br />
displayed besides a complete NER defect also sensitivity to crosslinking agents and<br />
an enhanced spontaneous and induced mutation rate [34]. Weeda et al reported that<br />
ERCCI MEFs display premature cellular senescence, with large polyploid nuclei in<br />
early passages, and many non-cycling cells [8]. Interestingly, neither established<br />
ERCCI-deficient hamster cells, nor ERCCI-/- ES cells (Weeda, unpublished data)<br />
display this phenotype, suggesting a relation between mortallimrnortal status of the<br />
cell. Premature cellular senescence is also not observed in any of the MEFs of the<br />
other NER mouse models analyzed (J. de Wit, unpublished data). Life span of<br />
ERCCI homozygote mouse mutants is strongly reduced. Two independent studies<br />
NER-deficient mouse models 37