Previous Article | Next Article ![]()
Molecular and Cellular Biology, May 2000, p. 3425-3433, Vol. 20, No. 10
CRC Drug-DNA Interactions Research Group,
Department of Oncology, Royal Free and University College Medical
School, University College London, London W1P 8BT, United Kingdom
Received 24 August 1999/Returned for modification 7 October
1999/Accepted 17 February 2000
Bifunctional alkylating agents and other drugs which produce DNA
interstrand cross-links (ICLs) are among the most effective antitumor
agents in clinical use. In contrast to agents which produce bulky
adducts on only one strand of the DNA, the cellular mechanisms which
act to eliminate DNA ICLs are still poorly understood, although
nucleotide excision repair is known to play a crucial role in an early
repair step. Using haploid Saccharomyces cerevisiae strains
disrupted for genes central to the recombination, nonhomologous end-joining (NHEJ), and mutagenesis pathways, all these activities were
found to be involved in the repair of nitrogen mustard
(mechlorethamine)- and cisplatin-induced DNA ICLs, but the particular
pathway employed is cell cycle dependent. Examination of whole
chromosomes from treated cells using contour-clamped homogenous
electric field electrophoresis revealed the intermediate in the repair
of ICLs in dividing cells, which are mostly in S phase, to be
double-strand breaks (DSBs). The origin of these breaks is not clear
since they were still efficiently induced in nucleotide excision and
base excision repair-deficient, mismatch repair-defective,
rad27 and mre11 disruptant strains. In
replicating cells, RAD52-dependent recombination and NHEJ
both act to repair the DSBs. In contrast, few DSBs were observed in
quiescent cells, and recombination therefore seems dispensable for
repair. The activity of the Rev3 protein (DNA polymerase
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Repair of Intermediate Structures Produced at DNA Interstrand
Cross-Links in Saccharomyces cerevisiae
) is
apparently more important for the processing of intermediates in
stationary-phase cells, since rev3 disruptants were more
sensitive in this phase than in the exponential growth phase.
*
Corresponding author. Mailing address: CRC Drug-DNA
Interactions Research Group, Department of Oncology, Royal Free and
University College Medical School, University College London, 91 Riding
House St., London W1P 8BT, United Kingdom. Phone: 44 20 7504 9319. Fax: 44 20 7436 2956. E-mail: p.mchugh{at}ucl.ac.uk.
This article has been cited by other articles:
| J. Bacteriol. | J. Virol. | Eukaryot. Cell |
|---|
| Microbiol. Mol. Biol. Rev. | Clin. Vaccine Immunol. | All ASM Journals |
|---|