PMID- 18603020
OWN - NLM
STAT- MEDLINE
DCOM- 20081216
LR  - 20211020
IS  - 1568-7864 (Print)
IS  - 1568-7856 (Linking)
VI  - 7
IP  - 10
DP  - 2008 Oct 1
TI  - Induction of intrachromosomal homologous recombination in human cells by 
      raltitrexed, an inhibitor of thymidylate synthase.
PG  - 1624-35
LID - 10.1016/j.dnarep.2008.06.006 [doi]
AB  - Thymidylate deprivation brings about "thymineless death" in prokaryotes and 
      eukaryotes. Although the precise mechanism for thymineless death has remained 
      elusive, inhibition of the enzyme thymidylate synthase (TS), which catalyzes the 
      de novo synthesis of TMP, has served for many years as a basis for 
      chemotherapeutic strategies. Numerous studies have identified a variety of 
      cellular responses to thymidylate deprivation, including disruption of DNA 
      replication and induction of DNA breaks. Since stalled or collapsed replication 
      forks and strand breaks are generally viewed as being recombinogenic, it is not 
      surprising that a link has been demonstrated between recombination induction and 
      thymidylate deprivation in bacteria and lower eukaryotes. A similar connection 
      between recombination and TS inhibition has been suggested by studies done in 
      mammalian cells, but the relationship between recombination and TS inhibition in 
      mammalian cells had not been demonstrated rigorously. To gain insight into the 
      mechanism of thymineless death in mammalian cells, in this work we undertook a 
      direct investigation of recombination in human cells treated with raltitrexed 
      (RTX), a folate analog that is a specific inhibitor of TS. Using a model system 
      to study intrachromosomal homologous recombination in cultured fibroblasts, we 
      provide definitive evidence that treatment with RTX can stimulate accurate 
      recombination events in human cells. Gene conversions not associated with 
      crossovers were specifically enhanced several-fold by RTX. Additional experiments 
      demonstrated that recombination events provoked by a double-strand break (DSB) 
      were not impacted by treatment with RTX, nor was error-prone DSB repair via 
      nonhomologous end-joining. Our work provides evidence that thymineless death in 
      human cells is not mediated by corruption of DSB repair processes and suggests 
      that an increase in chromosomal recombination may be an important element of 
      cellular responses leading to thymineless death.
FAU - Waldman, Barbara Criscuolo
AU  - Waldman BC
AD  - Department of Biological Sciences, University of South Carolina, Columbia, SC 
      29208, USA. awaldman@biol.sc.edu
FAU - Wang, Yibin
AU  - Wang Y
FAU - Kilaru, Kasturi
AU  - Kilaru K
FAU - Yang, Zhengguan
AU  - Yang Z
FAU - Bhasin, Alaukik
AU  - Bhasin A
FAU - Wyatt, Michael D
AU  - Wyatt MD
FAU - Waldman, Alan S
AU  - Waldman AS
LA  - eng
GR  - CA 100450/CA/NCI NIH HHS/United States
GR  - GM 081472/GM/NIGMS NIH HHS/United States
GR  - R01 CA100450/CA/NCI NIH HHS/United States
GR  - R01 GM047110-13/GM/NIGMS NIH HHS/United States
GR  - R01 CA100450-04/CA/NCI NIH HHS/United States
GR  - GM 47110/GM/NIGMS NIH HHS/United States
GR  - R01 CA100450-03/CA/NCI NIH HHS/United States
GR  - R01 CA100450-01A2/CA/NCI NIH HHS/United States
GR  - R01 GM047110/GM/NIGMS NIH HHS/United States
GR  - R01 CA100450-02/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20080721
PL  - Netherlands
TA  - DNA Repair (Amst)
JT  - DNA repair
JID - 101139138
RN  - 0 (Folic Acid Antagonists)
RN  - 0 (Quinazolines)
RN  - 0 (Thiophenes)
RN  - EC 2.1.1.45 (Thymidylate Synthase)
RN  - FCB9EGG971 (raltitrexed)
SB  - IM
MH  - Base Sequence
MH  - Blotting, Southern
MH  - Cell Line
MH  - Chromosomes, Human/enzymology/*metabolism
MH  - Crossing Over, Genetic/drug effects
MH  - DNA Breaks, Double-Stranded/drug effects
MH  - Fibroblasts/*drug effects/enzymology/*metabolism
MH  - Folic Acid Antagonists/*pharmacology
MH  - Gene Conversion/drug effects
MH  - Humans
MH  - Molecular Sequence Data
MH  - Polymerase Chain Reaction
MH  - Quinazolines/*pharmacology
MH  - Recombination, Genetic/*drug effects
MH  - Substrate Specificity/drug effects
MH  - Thiophenes/*pharmacology
MH  - Thymidylate Synthase/*antagonists & inhibitors/genetics
PMC - PMC2586641
MID - NIHMS73788
EDAT- 2008/07/08 09:00
MHDA- 2008/12/17 09:00
PMCR- 2009/10/01
CRDT- 2008/07/08 09:00
PHST- 2008/03/13 00:00 [received]
PHST- 2008/06/10 00:00 [revised]
PHST- 2008/06/10 00:00 [accepted]
PHST- 2008/07/08 09:00 [pubmed]
PHST- 2008/12/17 09:00 [medline]
PHST- 2008/07/08 09:00 [entrez]
PHST- 2009/10/01 00:00 [pmc-release]
AID - S1568-7864(08)00224-3 [pii]
AID - 10.1016/j.dnarep.2008.06.006 [doi]
PST - ppublish
SO  - DNA Repair (Amst). 2008 Oct 1;7(10):1624-35. doi: 10.1016/j.dnarep.2008.06.006. 
      Epub 2008 Jul 21.