The 89-kDa PARP1 cleavage fragment serves as a cytoplasmic PAR carrier to induce AIF-mediated apoptosis

Abstract

Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear protein that is activated by binding to DNA lesions and catalyzes poly(ADP-ribosyl)ation of nuclear acceptor proteins, including PARP1 itself, to recruit DNA repair machinery to DNA lesions. When excessive DNA damage occurs, poly(ADP-ribose) (PAR) produced by PARP1 is translocated to the cytoplasm, changing the activity and localization of cytoplasmic proteins, e.g., apoptosis-inducing factor (AIF), hexokinase, and resulting in cell death. This cascade, termed parthanatos, is a caspase-independent programmed cell death distinct from necrosis and apoptosis. In contrast, PARP1 is a substrate of activated caspases 3 and 7 in caspase-dependent apoptosis. Once cleaved, PARP1 loses its activity, thereby suppressing DNA repair. Caspase cleavage of PARP1 occurs within a nuclear localization signal near the DNA-binding domain, resulting in the formation of 24-kDa and 89-kDa fragments. In the present study, we found that caspase activation by staurosporine- and actinomycin D-induced PARP1 autopoly(ADP-ribosyl)ation and fragmentation, generating poly(ADP-ribosyl)ated 89-kDa and 24-kDa PARP1 fragments. The 89-kDa PARP1 fragments with covalently attached PAR polymers were translocated to the cytoplasm, whereas 24-kDa fragments remained associated with DNA lesions. In the cytoplasm, AIF binding to PAR attached to the 89-kDa PARP1 fragment facilitated its translocation to the nucleus. Thus, the 89-kDa PARP1 fragment is a PAR carrier to the cytoplasm, inducing AIF release from mitochondria. Elucidation of the caspase-mediated interaction between apoptosis and parthanatos pathways extend the current knowledge on mechanisms underlying programmed cell death and may lead to new therapeutic targets. Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear protein that is activated by binding to DNA lesions and catalyzes poly(ADP-ribosyl)ation of nuclear acceptor proteins, including PARP1 itself, to recruit DNA repair machinery to DNA lesions. When excessive DNA damage occurs, poly(ADP-ribose) (PAR) produced by PARP1 is translocated to the cytoplasm, changing the activity and localization of cytoplasmic proteins, e.g., apoptosis-inducing factor (AIF), hexokinase, and resulting in cell death. This cascade, termed parthanatos, is a caspase-independent programmed cell death distinct from necrosis and apoptosis. In contrast, PARP1 is a substrate of activated caspases 3 and 7 in caspase-dependent apoptosis. Once cleaved, PARP1 loses its activity, thereby suppressing DNA repair. Caspase cleavage of PARP1 occurs within a nuclear localization signal near the DNA-binding domain, resulting in the formation of 24-kDa and 89-kDa fragments. In the present study, we found that caspase activation by staurosporine- and actinomycin D-induced PARP1 autopoly(ADP-ribosyl)ation and fragmentation, generating poly(ADP-ribosyl)ated 89-kDa and 24-kDa PARP1 fragments. The 89-kDa PARP1 fragments with covalently attached PAR polymers were translocated to the cytoplasm, whereas 24-kDa fragments remained associated with DNA lesions. In the cytoplasm, AIF binding to PAR attached to the 89-kDa PARP1 fragment facilitated its translocation to the nucleus. Thus, the 89-kDa PARP1 fragment is a PAR carrier to the cytoplasm, inducing AIF release from mitochondria. Elucidation of the caspase-mediated interaction between apoptosis and parthanatos pathways extend the current knowledge on mechanisms underlying programmed cell death and may lead to new therapeutic targets. Poly(ADP-ribose) polymerase 1 (PARP1), in the presence of NAD+, catalyzes poly(ADP-ribosyl)ation, generating poly(ADP-ribose) (PAR) chains attached to acceptor proteins (1Ame J.C. Spenlehauer C. de Murcia G. The PARP superfamily.Bioessays. 2004; 26: 882-893Crossref PubMed Scopus (1113) Google Scholar, 2Gupte R. Liu Z. Kraus W.L. PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes.Genes Dev. 2017; 31: 101-126Crossref PubMed Scopus (261) Google Scholar). Activation of PARP1 catalytic activity occurs in response to DNA damage. Poly(ADP-ribosyl)ation of acceptor proteins modifies their activities, structure, and/or location, which affects diverse cellular functions, including DNA repair, gene expression, and cell death (1Ame J.C. Spenlehauer C. de Murcia G. The PARP superfamily.Bioessays. 2004; 26: 882-893Crossref PubMed Scopus (1113) Google Scholar, 2Gupte R. Liu Z. Kraus W.L. PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes.Genes Dev. 2017; 31: 101-126Crossref PubMed Scopus (261) Google Scholar, 3D'Amours D. Desnoyers S. D'Silva I. Poirier G.G. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions.Biochem. J. 1999; 342: 249-268Crossref PubMed Scopus (1481) Google Scholar, 4Gibson B.A. Kraus W.L. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs.Nat. Rev. Mol. Cell Biol. 2012; 13: 411-424Crossref PubMed Scopus (719) Google Scholar). PARP1 is a 116-kDa protein, consisting of three domains: DNA-binding domain (N terminal), automodification domain (central), and catalytic domain (C terminal) (1Ame J.C. Spenlehauer C. de Murcia G. The PARP superfamily.Bioessays. 2004; 26: 882-893Crossref PubMed Scopus (1113) Google Scholar). The DNA-binding domain recognizes DNA strand breaks, resulting in its dimerization and catalysis by the catalytic domain of transautomodification with PAR of the automodification domain (2Gupte R. Liu Z. Kraus W.L. PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes.Genes Dev. 2017; 31: 101-126Crossref PubMed Scopus (261) Google Scholar, 5Verheugd P. Butepage M. Eckei L. Luscher B. Players in ADP-ribosylation: readers and erasers.Curr. Protein Pept. Sci. 2016; 17: 654-667Crossref PubMed Scopus (23) Google Scholar). PARP1 possesses a nuclear localization sequence (NLS) near the DNA-binding domain and a caspase-cleavage site between the DNA-binding domain and the automodification domain (3D'Amours D. Desnoyers S. D'Silva I. Poirier G.G. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions.Biochem. J. 1999; 342: 249-268Crossref PubMed Scopus (1481) Google Scholar). PARP1 is initially responsible for DNA repair; the negative charge of PAR polymers covalently attached to PARP1 and histone loosen chromatin structure and recruit the scaffold protein XRCC1 and other DNA-remodeling enzymes (1Ame J.C. Spenlehauer C. de Murcia G. The PARP superfamily.Bioessays. 2004; 26: 882-893Crossref PubMed Scopus (1113) Google Scholar, 2Gupte R. Liu Z. Kraus W.L. PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes.Genes Dev. 2017; 31: 101-126Crossref PubMed Scopus (261) Google Scholar, 3D'Amours D. Desnoyers S. D'Silva I. Poirier G.G. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions.Biochem. J. 1999; 342: 249-268Crossref PubMed Scopus (1481) Google Scholar). During caspase-dependent apoptosis, PARP1 is cleaved by caspases 3 and 7 at its caspase-cleavage site into 24-kDa and 89-kDa fragments (6Salvesen G.S. Dixit V.M. Caspases: intracellular signaling by proteolysis.Cell. 1997; 91: 443-446Abstract Full Text Full Text PDF PubMed Scopus (1896) Google Scholar, 7Germain M. Affar E.B. D'Amours D. Dixit V.M. Salvesen G.S. Poirier G.G. Cleavage of automodified poly(ADP-ribose) polymerase during apoptosis. Evidence for involvement of caspase-7.J. Biol. Chem. 1999; 274: 28379-28384Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 8Kaufmann S.H. Desnoyers S. Ottaviano Y. Davidson N.E. Poirier G.G. Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis.Cancer Res. 1993; 53: 3976-3985PubMed Google Scholar). The 24-kDa PARP1 fragment contains the DNA-binding motif and the NLS, whereas the 89-kDa PARP1 fragment contains the automodification and catalytic domains. After PARP1 cleavage by caspase, the 24-kDa PARP1 fragment irreversibly binds to DNA breaks and acts as a transdominant inhibitor of active PARP1, whereas the 89-kDa PARP1 fragment is translocated to the cytoplasm (9Soldani C. Lazze M.C. Bottone M.G. Tognon G. Biggiogera M. Pellicciari C.E. Scovassi A.I. Poly(ADP-ribose) polymerase cleavage during apoptosis: when and where?.Exp. Cell Res. 2001; 269: 193-201Crossref PubMed Scopus (111) Google Scholar, 10Smulson M.E. Pang D. Jung M. Dimtchev A. Chasovskikh S. Spoonde A. Simbulan-Rosenthal C. Rosenthal D. Yakovlev A. Dritschilo A. Irreversible binding of poly(ADP)ribose polymerase cleavage product to DNA ends revealed by atomic force microscopy: possible role in apoptosis.Cancer Res. 1998; 58: 3495-3498PubMed Google Scholar). Thereby, PARP1 fragmentation by caspase leads to its inactivation, which inhibits DNA repair and facilitates caspase-mediated DNA fragmentation in apoptosis. Parthanatos, a programmed cell death, is initiated by PARP1 over-reaction to DNA damage, which is seen in neurons in Parkinson's disease, after glutamate excitotoxicity and in brain ischemia (11Andrabi S.A. Kang H.C. Haince J.F. Lee Y.I. Zhang J. Chi Z. West A.B. Koehler R.C. Poirier G.G. Dawson T.M. Dawson V.L. Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death.Nat. Med. 2011; 17: 692-699Crossref PubMed Scopus (144) Google Scholar, 12Lee Y. Karuppagounder S.S. Shin J.H. Lee Y.I. Ko H.S. Swing D. Jiang H. Kang S.U. Lee B.D. Kang H.C. Kim D. Tessarollo L. Dawson V.L. Dawson T.M. Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss.Nat. Neurosci. 2013; 16: 1392-1400Crossref PubMed Scopus (123) Google Scholar, 13Wang Y. Kim N.S. Haince J.F. Kang H.C. David K.K. Andrabi S.A. Poirier G.G. Dawson V.L. Dawson T.M. Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos).Sci. Signal. 2011; 4: ra20Crossref PubMed Scopus (257) Google Scholar). Suppression of parthanatos through PARP1 inhibition may have therapeutic potential in these diseases (14Fatokun A.A. Dawson V.L. Dawson T.M. Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities.Br. J. Pharmacol. 2014; 171: 2000-2016Crossref PubMed Scopus (261) Google Scholar). On binding single- and double-stranded DNA breaks, activated PARP1 catalyzes the covalent addition of long and branched polymers of ADP-ribose to nuclear acceptor proteins, including PARP1 itself, XRCC1, and histones (1Ame J.C. Spenlehauer C. de Murcia G. The PARP superfamily.Bioessays. 2004; 26: 882-893Crossref PubMed Scopus (1113) Google Scholar, 2Gupte R. Liu Z. Kraus W.L. PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes.Genes Dev. 2017; 31: 101-126Crossref PubMed Scopus (261) Google Scholar). PAR translocation from the nucleus to the cytoplasm is a crucial step in the parthanatos pathway. After DNA damage, 90% of PAR polymers are synthesized by PARP1, and most PAR polymers are attached to PARP1 itself (1Ame J.C. Spenlehauer C. de Murcia G. The PARP superfamily.Bioessays. 2004; 26: 882-893Crossref PubMed Scopus (1113) Google Scholar). Poly(ADP-ribose) glycohydrolase, a primary enzyme for PAR degradation, is involved in PAR translocation from the nucleus to cytoplasm (15Mashimo M. J. J. 3 and cell death during Sci. S. A. 2013; PubMed Scopus Google Scholar, M. J. J. and of the of 2014; PubMed Scopus Google Scholar, M. J. role of 3 in poly(ADP-ribose) response to Protein Pept. Sci. 2016; 17: PubMed Scopus Google Scholar). Poly(ADP-ribose) activity and PAR polymers that to nuclear (15Mashimo M. J. J. 3 and cell death during Sci. S. A. 2013; PubMed Scopus Google Scholar, M. J. role of 3 in poly(ADP-ribose) response to Protein Pept. Sci. 2016; 17: PubMed Scopus Google Scholar, M. J. H. A. C. D. J. PARP1 inhibition in and 4: PubMed Scopus Google Scholar). After PAR polymers produced by PARP1 are translocated from the nucleus to the cytoplasm, to apoptosis-inducing factor (AIF), which is to the (15Mashimo M. J. J. 3 and cell death during Sci. S. A. 2013; PubMed Scopus Google Scholar, S.A. Kim N.S. H. M. Zhang Z. Koehler R.C. Poirier G.G. Dawson V.L. Dawson T.M. Poly(ADP-ribose) (PAR) is a death Sci. S. A. PubMed Scopus Google Scholar). PAR binding to AIF in its release to the cytoplasm Y. Kim N.S. Haince J.F. Kang H.C. David K.K. Andrabi S.A. Poirier G.G. Dawson V.L. Dawson T.M. Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos).Sci. Signal. 2011; 4: ra20Crossref PubMed Scopus (257) Google Scholar). AIF an near its AIF is translocated to the nucleus and with resulting in DNA fragmentation Y. R. H. Kim B. L. C. R. Z. that mediates cell death by DNA damage and poly(ADP-ribose) 2016; PubMed Scopus Google Scholar). PAR with which is the enzyme in the and inhibits its activity, to S.A. C. Karuppagounder S.S. Poirier G.G. Dawson V.L. Dawson T.M. Poly(ADP-ribose) occurs through inhibition of Sci. S. A. 2014; PubMed Scopus Google Scholar). including PAR and its translocation to parthanatos, are caspase H. C. Poirier G.G. Dawson T.M. Dawson V.L. of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing PubMed Scopus Google Scholar). the AIF release and its translocation to the cytoplasm during apoptosis in response to in diverse cell D. factor in and the of a Full Text Full Text PDF PubMed Scopus Google Scholar). as and a of through the formation of which AIF release from H. S. Z. of AIF in response to on at the J. PubMed Scopus Google Scholar). a AIF from by which DNA fragmentation G. A. cleavage and release of apoptosis-inducing factor from Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In study, we a for AIF release during apoptosis. activation after to and actinomycin apoptosis in PAR and PARP1 cleavage into 89-kDa and 24-kDa PARP1 fragments. The 89-kDa PARP1 with attached PAR were translocated from the nucleus to the cytoplasm, whereas 24-kDa fragments were associated with DNA The 89-kDa PARP1 fragments in the cytoplasm with AIF their PAR to AIF release and translocation to the resulting in nuclear Thus, the 89-kDa PARP1 fragment by acts as a PAR carrier from the nucleus to the cytoplasm to DNA fragmentation in caspase-mediated apoptosis. an apoptosis cell death. of to for in inhibition of PARP by and the of whereas inhibition of caspase by cell death the seen with In to the of PARP1 inhibition by inhibition of by the to to the seen with of PARP1 PARP1 protein to of that in with PARP1 with to that seen with In with the of PARP1 that to cell death by to a in and caspase-independent cell death, PARP1 activation in PAR and AIF release from H. C. Poirier G.G. Dawson T.M. Dawson V.L. of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing PubMed Scopus Google Scholar). revealed that PAR as early as 1 after to and the at with PAR at After to for AIF in cell to nuclear The inhibition of caspase PARP1 PAR as as nuclear PARP1 PAR AIF translocation to and nuclear are with the that PARP1 activation and AIF release from to of caspase-mediated apoptosis after PARP1 is cleaved near the domain by and 7 into 24-kDa and 89-kDa PARP1 fragments (6Salvesen G.S. Dixit V.M. Caspases: intracellular signaling by proteolysis.Cell. 1997; 91: 443-446Abstract Full Text Full Text PDF PubMed Scopus (1896) Google Scholar). the PARP1 which recognizes PARP1 and its 89-kDa PARP1 89-kDa PARP1 fragments after a to which in activation activation as as PARP1 fragmentation after and of PARP1 by activation to intracellular localization of PARP1 and we found after to PARP1 translocated from the nucleus to the cytoplasm after 3 in contrast, PAR in the of at 1 and translocated to the cytoplasm after 3 and cytoplasmic PAR after to whereas the cytoplasmic localization of PARP1 PARP1 translocation of PAR to the cytoplasm after to with the molecular of after to the 89-kDa PARP1 PARP1, in the cytoplasm PARP1 fragmentation and the cytoplasmic localization of 89-kDa PARP1 fragments that of PARP1 present as the cleaved in the cytoplasm that the 89-kDa PARP1 fragment is translocated to the cytoplasm after PAR in the localization of 89-kDa and 24-kDa PARP1 fragments after to and were to the and of PARP1, generating and After to the signal in the cytoplasm and whereas signal to the nucleus are with the that 89-kDa PARP1 24-kDa PARP1 are translocated to the cytoplasm after PARP1 cleavage by The of PARP1 at DNA lesions is for PAR J.C. H. poly(ADP-ribosyl)ation by is for response to DNA damage in Res. PubMed Scopus Google Scholar). PARP1 is cleaved after is to DNA lesions. we a to DNA lesions in PARP1 After and at and to and at DNA whereas the In contrast, at DNA lesions in the presence of for a in the of whereas its The of by the addition of to the seen with that caspases PARP1 that is at DNA lesions after fragmentation, 89-kDa PARP1 fragments whereas 24-kDa PARP1 fragments at the DNA lesions. on the that caspase PARP1 after is to DNA lesions and that the 89-kDa PARP1 fragment possesses the automodification domain, we that 89-kDa PARP1 fragments were translocated to the cytoplasm with attached PAR we a a on The is a motif in binds proteins, which in a PARP1 proteins automodified by PAR polymers were with proteins for 1 the PARP1 and 89-kDa PARP1 fragments PAR polymers with attached 89-kDa PARP1 fragments were to a molecular the PARP1 that 89-kDa PARP1 fragments by PAR In after to 89-kDa PARP1 fragments present in the cytoplasm were poly(ADP-ribosyl)ated the of 89-kDa PARP1 fragments and its translocation to the cytoplasm formation of poly(ADP-ribosyl)ated 89-kDa PARP1 fragments 89-kDa PARP1 fragments after PAR polymers from the nucleus to the cytoplasm, we a PARP1 which is a the caspase-cleavage site In PARP1 in the translocation of PARP1 and PAR to the cytoplasm after PARP1 at and of the presence of are with the that of the 89-kDa PARP1 fragment by caspase cleavage is for PAR translocation to the In the cytoplasm, PAR binding to AIF is a critical step involved in the release of AIF from S.A. Kim N.S. H. M. Zhang Z. Koehler R.C. Poirier G.G. Dawson V.L. Dawson T.M. Poly(ADP-ribose) (PAR) is a death Sci. S. A. PubMed Scopus Google Scholar). 89-kDa PARP1 fragments with AIF PAR polymers after translocation to the After to the 89-kDa PARP1 the PARP1, with AIF in cytoplasm, the 89-kDa PARP1 fragments with which by with that PARP1 fragments with AIF in cytoplasmic and after a to that the 89-kDa PARP1 fragments with AIF in the cytoplasm PAR PARP1 a in the catalytic domain and loses the to poly(ADP-ribosyl)ation In PARP1 of PARP1 PAR after to as seen with PARP1 a caspase-cleavage in the cleavage of PARP1 as seen with In PARP1 cleaved after a to these the the poly(ADP-ribosyl)ation of and cleaved of PARP1 with and poly(ADP-ribosyl)ation of PARP1 that caspase, which is activated by PARP1, resulting in its dimerization with PARP1 and transautomodification with In PARP1 in the translocation of PARP1 to the cytoplasm by PAR to in the cleavage of and PARP1 which were translocated to the cytoplasm of their cleaved were in the cytoplasm the cleaved of PARP1 in the cytoplasm automodified by PAR and with AIF that transautomodification of PARP1 by PAR and its fragmentation by caspase are for AIF the 89-kDa PARP1 fragment acts as a carrier for PAR translocation from the nucleus to the cytoplasm in caspase-dependent apoptosis by apoptosis actinomycin which inhibits and PARP1 actinomycin D-induced In contrast, the D-induced apoptosis through cell in actinomycin PAR in the nucleus and its translocation to the cytoplasm, AIF translocation from to the and nuclear whereas and these to actinomycin in PARP1 fragmentation with activation After PARP1 fragmentation by actinomycin 89-kDa PARP1 24-kDa PARP1 were translocated to the cytoplasm after fragmentation by translocated to the cytoplasm After to actinomycin of the 89-kDa PARP1 PARP1, in the cytoplasm PARP1 fragmentation and the cytoplasmic localization of 89-kDa PARP1 fragments In the cytoplasm, 89-kDa PARP1 fragments were by PAR and with in a that by with that the 89-kDa PARP1 fragment is as a PAR carrier to AIF release from in caspase-dependent apoptosis. PARP1 fragmentation after caspase activation is as an early in apoptosis (6Salvesen G.S. Dixit V.M. Caspases: intracellular signaling by proteolysis.Cell. 1997; 91: 443-446Abstract Full Text Full Text PDF PubMed Scopus (1896) Google Scholar, 8Kaufmann S.H. Desnoyers S. Ottaviano Y. Davidson N.E. Poirier G.G. Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis.Cancer Res. 1993; 53: 3976-3985PubMed Google Scholar). The primary of PARP1 is to and repair DNA breaks J.C. de Murcia G. functions for an Rev. Mol. Cell Biol. PubMed Scopus Google Scholar). PARP1 binds to breaks and PAR polymers to PARP1 itself, which DNA repair machinery to DNA lesions (3D'Amours D. Desnoyers S. D'Silva I. Poirier G.G. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions.Biochem. J. 1999; 342: 249-268Crossref PubMed Scopus (1481) Google Scholar, 5Verheugd P. Butepage M. Eckei L. Luscher B. Players in ADP-ribosylation: readers and erasers.Curr. Protein Pept. Sci. 2016; 17: 654-667Crossref PubMed Scopus (23) Google Scholar, J.C. de Murcia G. functions for an Rev. Mol. Cell Biol. PubMed Scopus Google Scholar). PARP1 formation of PAR on its in chromatin as a of the negative charge of the which chromatin to the of machinery to DNA breaks P. Butepage M. Eckei L. Luscher B. Players in ADP-ribosylation: readers and erasers.Curr. Protein Pept. Sci. 2016; 17: 654-667Crossref PubMed Scopus (23) Google Scholar, J.C. de Murcia G. functions for an Rev. Mol. Cell Biol. PubMed Scopus Google Scholar). PARP1 fragmentation by caspase to apoptosis by these In study, we for the that PARP1 fragmentation by caspase is to 89-kDa PARP fragments that of PAR to the cytoplasm to DNA fragmentation in a caspase-dependent PAR after to and actinomycin by with and whereas caspase cleavage by with that PARP1 activated by DNA fragmentation, resulting from the activation of PAR After to when and cleaved PARP1 in and with the DNA by with whereas PARP1 a of PARP1 in caspase 3 cleavage the as the that caspase PARP1 after PARP1 binds breaks and that the 89-kDa PARP1 fragment is from DNA lesions the DNA-binding of the 24-kDa PARP1 as PARP1 PAR after binding cleaved by caspase after PAR and PAR formation on the automodification In we that the 89-kDa PARP1 fragment in the cytoplasm PAR and that its interaction with AIF In contrast, a to in of to the DNA The that the 24-kDa PARP1 fragment is of DNA binding and to The presence of the 24-kDa PARP1 fragment PARP1 from binding to the DNA to DNA repair, thereby apoptosis. This is by binding to DNA of 24-kDa PARP1 fragments by M.E. Pang D. Jung M. Dimtchev A. Chasovskikh S. Spoonde A. Simbulan-Rosenthal C. Rosenthal D. Yakovlev A. Dritschilo A. Irreversible binding of poly(ADP)ribose polymerase cleavage product to DNA ends revealed by atomic force microscopy: possible role in apoptosis.Cancer Res. 1998; 58: 3495-3498PubMed Google Scholar). Parthanatos to in neuronal cell death in Parkinson's and after brain (11Andrabi S.A. Kang H.C. Haince J.F. Lee Y.I. Zhang J. Chi Z. West A.B. Koehler R.C. Poirier G.G. Dawson T.M. Dawson V.L. Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death.Nat. Med. 2011; 17: 692-699Crossref PubMed Scopus (144) Google Scholar, 12Lee Y. Karuppagounder S.S. Shin J.H. Lee Y.I. Ko H.S. Swing D. Jiang H. Kang S.U. Lee B.D. Kang H.C. Kim D. Tessarollo L. Dawson V.L. Dawson T.M. Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss.Nat. 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PubMed Scopus Google Scholar). and are which are with from and and are involved in and with and by inducing programmed cell death L. M.C. R. R. Cell death mechanisms by Mol. PubMed Scopus Google Scholar). PARP1 after whereas the sequence of PARP1 as P. D. D. Zhang D. A. J. The and PubMed Scopus Google Scholar). caspase-independent apoptosis and AIF release from R. of and release the of of caspase activation during 13: PubMed Scopus Google Scholar). Thus, caspase-independent apoptosis by 89-kDa PARP1 fragments that as PAR by the as that seen in In we that PARP1 fragmentation by caspase an 89-kDa PARP1 fragment that as a PAR carrier from the nucleus to the cytoplasm to apoptosis. and were from and from Cell from from from and and and and and from PARP1 and were from PARP1 and PARP1 were with and and and by of were in of and of at in a with PARP1 into were with the and in with were in with 1 of were on and for 1 to the of and actinomycin PARP inhibitor and caspase inhibitor were for and actinomycin Cell were cell to the by at on were in with with and and with and After with primary were with three with and with of to of primary were with a with an were with of on a were with PARP1 PARP1 and to the After of PARP1 by a with an with a to for 1 at in within the nucleus. The with a to were at for to DNA damage. on a were in with Cell were with in inhibitor After of protein a cell were to and to The were with for at and with primary After with and with the for The of with were with a in 1 and inhibitor Cell were at for to the nuclear and which to the cytoplasmic and The at for to the cytoplasmic The nuclear in of and and with of The on of and by of After at for the as the nuclear in by at for from in by with with to the in its automodification domain as M. J. by the of Mol. Biol. PubMed Scopus Google Scholar). PARP1 automodified by PAR with in of and for at PARP1 and cytoplasmic were with of on in of inhibitor and at on a After three with were with in a were in with After actinomycin for cell were with 1 and inhibitor and were covalently to Protein to the and were with in with at for 1 to the Cell were with at for 1 After three with were with and with are of from the of were were three are within the and in the The that have of with the of M. M. and M. M. A. A. A. M. S. R. and M. M. and J. M. the S. and J. This by a for from the of and of J. and J. M. were by the of and

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