Nucleic Acids Research, Vol 27, Issue 16 3259-3266, Copyright © 1999 by Oxford University Press
PJ McHugh, RD Gill, R Waters and JA Hartley
The bifunctional alkylating anticancer drug nitrogen mustard forms a
variety of DNA lesions, including monoadducts and intrastrand and
interstrand crosslinks. Although it is known that nucleotide excision
repair (NER) is important in processing these adducts, the role of the
other principal excision repair pathway, base excision repair (BER) is less
well defined. Using isogenic Saccharomyces cerevisiae strains disrupted for
a variety of NER and BER genes we have examined the relative importance of
the two pathways in the repair of nitrogen mustard adducts. As expected,
NER defective cells (rad4 and rad14 strains) are extremely sensitive to the
drug. One of the BER mutants, a 3-methyladenine glycosylase defective
(mag1) strain also shows significant hypersensitivity. Using a rad4/mag1
double mutant it is shown that the two excision repair pathways are
epistatic to each other for nitrogen mustard sensitivity. Furthermore, both
rad14 and mag1 disruptants show elevated levels of nitrogen mustard-induced
forward mutation. Measurements of repair rates of nitrogen mustard N-
alkylpurine adducts in the highly transcribed RPB2 gene demonstrate defects
in the processing of mono-adducts in rad4, rad14 and mag1 strains. However,
there are differences in the kinetics of adduct removal in the NER mutants
compared to the mag1 strain. In the mag1 strain significant repair occurs
within 1 h with evidence of enhanced repair on the transcribed strand.
Adducts however accumulate at later times in this strain. In contrast, in
the NER mutants repair is only evident at times greater than 1 h. In a
mag1/rad4 double mutant damage accumulates with no evidence of repair.
Comparison of the rates of repair in this gene with those in a different
genomic region indicate that the contributions of NER and BER to the repair
of nitrogen mustard adducts may not be the same genome wide.
ARTICLES
Excision repair of nitrogen mustard-DNA adducts in Saccharomyces cerevisiae
CRC Drug-DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, 91 Riding House Street, London W1P 8BT, UK and. p.mchugh@ucl.ac.uk
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  N. Bhagwat, A. L. Olsen, A. T. Wang, K. Hanada, P. Stuckert, R. Kanaar, A. D'Andrea, L. J. Niedernhofer, and P. J. McHugh XPF-ERCC1 Participates in the Fanconi Anemia Pathway of Cross-Link Repair Mol. Cell. Biol., December 15, 2009; 29(24): 6427 - 6437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Liu, R. S. Nairn, and K. M. Vasquez Processing of triplex-directed psoralen DNA interstrand crosslinks by recombination mechanisms Nucleic Acids Res., August 1, 2008; 36(14): 4680 - 4688. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Pamidi, R. Cardoso, A. Hakem, E. Matysiak-Zablocki, A. Poonepalli, L. Tamblyn, B. Perez-Ordonez, M. P. Hande, O. Sanchez, and R. Hakem Functional Interplay of p53 and Mus81 in DNA Damage Responses and Cancer Cancer Res., September 15, 2007; 67(18): 8527 - 8535. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Zhang, R. Kaur, X. Lu, X. Shen, L. Li, and R. J. Legerski The Pso4 mRNA Splicing and DNA Repair Complex Interacts with WRN for Processing of DNA Interstrand Cross-links J. Biol. Chem., December 9, 2005; 280(49): 40559 - 40567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Barber, T. A. Ward, J. A. Hartley, and P. J. McHugh DNA Interstrand Cross-Link Repair in the Saccharomyces cerevisiae Cell Cycle: Overlapping Roles for PSO2 (SNM1) with MutS Factors and EXO1 during S Phase Mol. Cell. Biol., March 15, 2005; 25(6): 2297 - 2309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Kennedy, J. E. Quinn, P. B. Mullan, P. G. Johnston, and D. P. Harkin The Role of BRCA1 in the Cellular Response to Chemotherapy J Natl Cancer Inst, November 17, 2004; 96(22): 1659 - 1668. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Lambert, S. J. Mason, L. J. Barber, J. A. Hartley, J. A. Pearce, A. M. Carr, and P. J. McHugh Schizosaccharomyces pombe Checkpoint Response to DNA Interstrand Cross-Links Mol. Cell. Biol., July 1, 2003; 23(13): 4728 - 4737. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Marti, C. Kunz, and O. Fleck Repair of Damaged and Mismatched DNA by the XPC Homologues Rhp41 and Rhp42 of Fission Yeast Genetics, June 1, 2003; 164(2): 457 - 467. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kiakos, T. T. Howard, M. Lee, J. A. Hartley, and P. J. McHugh Saccharomyces cerevisiae RAD5 Influences the Excision Repair of DNA Minor Groove Adducts J. Biol. Chem., November 8, 2002; 277(46): 44576 - 44581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Cai, S. M. Ludeman, L. R. Wilson, A. B. Chung, and M. E. Dolan Effect of O6-Benzylguanine on Nitrogen Mustard-induced Toxicity, Apoptosis, and Mutagenicity in Chinese Hamster Ovary Cells Mol. Cancer Ther., November 1, 2001; 1(1): 21 - 28. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. McHugh, W. R. Sones, and J. A. Hartley Repair of Intermediate Structures Produced at DNA Interstrand Cross-Links in Saccharomyces cerevisiae Mol. Cell. Biol., May 15, 2000; 20(10): 3425 - 3433. [Abstract] [Full Text]
|
|