PMID- 20096707
OWN - NLM
STAT- MEDLINE
DCOM- 20100506
LR  - 20220309
IS  - 0027-5107 (Print)
IS  - 1873-135X (Electronic)
IS  - 0027-5107 (Linking)
VI  - 686
IP  - 1-2
DP  - 2010 Apr 1
TI  - Parp1 activation in mouse embryonic fibroblasts promotes Pol beta-dependent 
      cellular hypersensitivity to alkylation damage.
PG  - 57-67
LID - 10.1016/j.mrfmmm.2010.01.016 [doi]
AB  - Alkylating agents induce cell death in wild-type (WT) mouse embryonic fibroblasts 
      (MEFs) by multiple mechanisms, including apoptosis, autophagy and necrosis. DNA 
      polymerase beta (Pol beta) knockout (KO) MEFs are hypersensitive to the cytotoxic 
      effect of alkylating agents, as compared to WT MEFs. To test the hypothesis that 
      Parp1 is preferentially activated by methyl methanesulfonate (MMS) exposure of 
      Pol beta KO MEFs, we have examined the relationship between Pol beta expression, 
      Parp1 activation and cell survival following MMS exposure in a series of WT and 
      Pol beta deficient MEF cell lines. Consistent with our hypothesis, we observed 
      elevated Parp1 activation in Pol beta KO MEFs as compared to matched WT MEFs. 
      Both the MMS-induced activation of Parp1 and the MMS-induced cytotoxicity of Pol 
      beta KO MEFs are attenuated by pre-treatment with the Parp1/Parp2 inhibitor PJ34. 
      Further, elevated Parp1 activation is observed following knockdown (KD) of 
      endogenous Pol beta, as compared to WT cells. Pol beta KD MEFs are hypersensitive 
      to MMS and both the MMS-induced hypersensitivity and Parp1 activation is 
      prevented by pre-treatment with PJ34. In addition, the MMS-induced cellular 
      sensitivity of Pol beta KO MEFs is reversed when Parp1 is also deleted (Pol 
      beta/Parp1 double KO MEFs) and we observe no MMS sensitivity differential between 
      Pol beta/Parp1 double KO MEFs and those that express recombinant mouse Pol beta. 
      These studies suggest that Parp1 may function as a sensor of BER to initiate cell 
      death when BER is aborted or fails. Parp1 may therefore function in BER as a 
      tumor suppressor by initiating cell death and preventing the accumulation of 
      cells with chromosomal damage due to a BER defect.
CI  - Copyright 2010 Elsevier B.V. All rights reserved.
FAU - Jelezcova, Elena
AU  - Jelezcova E
AD  - Department of Pharmacology & Chemical Biology, University of Pittsburgh School of 
      Medicine & University of Pittsburgh Cancer Institute, Hillman Cancer Center, 
      Pittsburgh, PA 15213, USA.
FAU - Trivedi, Ram N
AU  - Trivedi RN
FAU - Wang, Xiao-Hong
AU  - Wang XH
FAU - Tang, Jiang-Bo
AU  - Tang JB
FAU - Brown, Ashley R
AU  - Brown AR
FAU - Goellner, Eva M
AU  - Goellner EM
FAU - Schamus, Sandy
AU  - Schamus S
FAU - Fornsaglio, Jamie L
AU  - Fornsaglio JL
FAU - Sobol, Robert W
AU  - Sobol RW
LA  - eng
GR  - P50 CA097190-01A10005/CA/NCI NIH HHS/United States
GR  - 1 R01 AG24364-01/AG/NIA NIH HHS/United States
GR  - R01 AG024364-05/AG/NIA NIH HHS/United States
GR  - 1 P20 CA132385-01/CA/NCI NIH HHS/United States
GR  - P20 CA132385/CA/NCI NIH HHS/United States
GR  - P20 CA103730-01/CA/NCI NIH HHS/United States
GR  - P20 CA103730/CA/NCI NIH HHS/United States
GR  - R01 AG024364/AG/NIA NIH HHS/United States
GR  - 1P50 CA 097190 01A1/CA/NCI NIH HHS/United States
GR  - P50 CA097190/CA/NCI NIH HHS/United States
GR  - P20 CA132385-03/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100122
PL  - Netherlands
TA  - Mutat Res
JT  - Mutation research
JID - 0400763
RN  - EC 2.4.2.30 (PARP1 protein, human)
RN  - EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - EC 2.7.7.7 (DNA Polymerase beta)
SB  - IM
MH  - Alkylation
MH  - Animals
MH  - Cell Death
MH  - Cell Line
MH  - DNA Damage
MH  - DNA Polymerase beta/*metabolism
MH  - *DNA Repair
MH  - Embryo, Mammalian
MH  - Fibroblasts/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Poly (ADP-Ribose) Polymerase-1
MH  - Poly(ADP-ribose) Polymerases/*metabolism
MH  - Up-Regulation
PMC - PMC2834876
MID - NIHMS172415
COIS- Conflict of interest statement: The authors state that there is no conflict of 
      interest.
EDAT- 2010/01/26 06:00
MHDA- 2010/05/07 06:00
PMCR- 2011/04/01
CRDT- 2010/01/26 06:00
PHST- 2009/11/11 00:00 [received]
PHST- 2010/01/10 00:00 [revised]
PHST- 2010/01/14 00:00 [accepted]
PHST- 2010/01/26 06:00 [entrez]
PHST- 2010/01/26 06:00 [pubmed]
PHST- 2010/05/07 06:00 [medline]
PHST- 2011/04/01 00:00 [pmc-release]
AID - S0027-5107(10)00038-2 [pii]
AID - 10.1016/j.mrfmmm.2010.01.016 [doi]
PST - ppublish
SO  - Mutat Res. 2010 Apr 1;686(1-2):57-67. doi: 10.1016/j.mrfmmm.2010.01.016. Epub 
      2010 Jan 22.