PMID- 10497198
OWN - NLM
STAT- MEDLINE
DCOM- 19991102
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 40
DP  - 1999 Oct 1
TI  - Cleavage of automodified poly(ADP-ribose) polymerase during apoptosis. Evidence 
      for involvement of caspase-7.
PG  - 28379-84
AB  - The abundant nuclear enzyme poly(ADP-ribose) polymerase (PARP) synthesizes 
      poly(ADP-ribose) in response to DNA strand breaks. During almost all forms of 
      apoptosis, PARP is cleaved by caspases, suggesting the crucial role of its 
      inactivation. A few studies have also reported a stimulation of PARP during 
      apoptosis. However, the role of PARP stimulation and cleavage during this cell 
      death process remains poorly understood. Here, we measured the stimulation of 
      endogenous poly(ADP-ribose) synthesis during VP-16-induced apoptosis in HL60 
      cells and found that PARP was cleaved by caspases at the time of its 
      poly(ADP-ribosyl)ation. In vitro experiments showed that PARP cleavage by 
      caspase-7, but not by caspase-3, was stimulated by its automodification by long 
      and branched poly(ADP-ribose). Consistently, caspase-7 exhibited an affinity for 
      poly(ADP-ribose), whereas caspase-3 did not. In addition, caspase-7 was activated 
      and accumulated in the nucleus of HL60 cells in response to the VP-16 treatment. 
      Furthermore, caspase-7 activation was concommitant with PARP cleavage in the 
      caspase-3-deficient cell line MCF-7 in response to staurosporine treatment. These 
      results strongly suggest that, in vivo, it is caspase-7 that is responsible for 
      PARP cleavage and that poly(ADP-ribosyl)ation of PARP accelerates its 
      proteolysis. Cleavage of the active form of caspase substrates could be a general 
      feature of the apoptotic process, ensuring the rapid inactivation of stress 
      signaling proteins.
FAU - Germain, M
AU  - Germain M
AD  - Health and Environment Unit, Laval University Medical Research Center, Centre 
      Hospitalier Universitaire de Quebec, Ste-Foy, Quebec G1V 4G2, Canada.
FAU - Affar, E B
AU  - Affar EB
FAU - D'Amours, D
AU  - D'Amours D
FAU - Dixit, V M
AU  - Dixit VM
FAU - Salvesen, G S
AU  - Salvesen GS
FAU - Poirier, G G
AU  - Poirier GG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (CASP7 protein, human)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspase 7)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - *Apoptosis
MH  - Caspase 3
MH  - Caspase 7
MH  - Caspases/*metabolism
MH  - Enzyme Activation
MH  - HL-60 Cells
MH  - Humans
MH  - Hydrolysis
MH  - Poly(ADP-ribose) Polymerases/*metabolism
EDAT- 1999/09/25 00:00
MHDA- 1999/09/25 00:01
CRDT- 1999/09/25 00:00
PHST- 1999/09/25 00:00 [pubmed]
PHST- 1999/09/25 00:01 [medline]
PHST- 1999/09/25 00:00 [entrez]
AID - S0021-9258(19)52061-0 [pii]
AID - 10.1074/jbc.274.40.28379 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 Oct 1;274(40):28379-84. doi: 10.1074/jbc.274.40.28379.