DOI: 10.1073/pnas.0606526103. Poly(ADP-ribose) (PAR) polymer is a death signal

Poly(ADP-ribose) (PAR) polymer is a death signal

10.1073/pnas.0606526103

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Excessive activation of the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP-1) plays a prominent role in various of models of cellular injury. Here, we identify poly(ADP-ribose) (PAR) polymer, a product of PARP-1 activity, as a previously uncharacterized cell death signal. PAR polymer is directly toxic to neurons, and degradation of PAR polymer by poly(ADP-ribose) glycohydrolase (PARG) or phosphodiesterase 1 prevents PAR polymer-induced cell death. PARP-1-dependent, NMDA excitotoxicity of cortical neurons is reduced by neutralizing antibodies to PAR and by overexpression of PARG. Neuronal cultures with reduced levels of PARG are more sensitive to NMDA excitotoxicity than WT cultures. Transgenic mice overexpressing PARG have significantly reduced infarct volumes after focal ischemia. Conversely, mice with reduced levels of PARG have significantly increased infarct volumes after focal ischemia compared with WT littermate controls. These results reveal PAR polymer as a signaling molecule that induces cell death and suggests that interference with PAR polymer signaling may offer innovative therapeutic approaches for the treatment of cellular injury.

Bibliography

Andrabi, S. A., Kim, N. S., Yu, S.-W., Wang, H., Koh, D. W., Sasaki, M., Klaus, J. A., Otsuka, T., Zhang, Z., Koehler, R. C., Hurn, P. D., Poirier, G. G., Dawson, V. L., & Dawson, T. M. (2006). Poly(ADP-ribose) (PAR) polymer is a death signal. Proceedings of the National Academy of Sciences, 103(48), 18308â18313.

Authors 14

Shaida A. Andrabi (first)
No Soo Kim (additional)
Seong-Woon Yu (additional)
Hongmin Wang (additional)
David W. Koh (additional)
Masayuki Sasaki (additional)
Judith A. Klaus (additional)
Takashi Otsuka (additional)
Zhizheng Zhang (additional)
Raymond C. Koehler (additional)
Patricia D. Hurn (additional)
Guy G. Poirier (additional)
Valina L. Dawson (additional)
Ted M. Dawson (additional)

References 34 Referenced 545

10.1016/j.nbd.2003.08.008
10.1016/S0165-6147(98)01193-6
10.1016/S0921-8777(00)00016-1
10.1016/S0065-2571(99)00024-2
10.1086/302389
10.1007/BF00928438
10.1023/A:1022316914492
10.1007/s00018-002-8527-2
10.1074/jbc.272.18.11895
10.1124/pr.54.3.375
10.1038/nm1097-1089
10.1523/JNEUROSCI.20-21-08005.2000
10.2307/3576299
10.1038/294284a0
10.1073/pnas.0406182101
10.1073/pnas.2237114100
10.1073/pnas.96.10.5774
10.1126/science.1072221
10.1523/JNEUROSCI.3461-04.2004
10.1523/JNEUROSCI.18-06-02040.1998
10.1074/jbc.M104920200
10.1021/bi00385a042
10.1006/abio.1993.1004
10.1006/excr.1998.4321
10.1016/S0021-9258(19)42597-0
10.1016/j.yexcr.2004.03.050
10.1042/BJ20040942
10.1161/01.STR.0000014203.65693.1E
10.1523/JNEUROSCI.13-06-02651.1993
10.1016/S0304-4165(99)00054-9
JF Haince, GG Poirier, JB Kirkland Current Protocols in Cell Biology, eds JS Bonifacion, M Dasso, JB Harford, J Lippincott-Schwartz, K Yamada (Wiley, Indianapolis, Unit 18.7. (2005). / Current Protocols in Cell Biology by Haince JF (2005)
10.4067/S0717-95022003000300006
10.1161/01.STR.20.1.84
10.1161/01.STR.0000163083.59201.34

Dates

Type	When
Created	18 years, 9 months ago (Nov. 20, 2006, 8:57 p.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 3:20 p.m.)
Indexed	2 days ago (Aug. 31, 2025, 6:08 a.m.)
Issued	18 years, 9 months ago (Nov. 28, 2006)
Published	18 years, 9 months ago (Nov. 28, 2006)
Published Online	18 years, 9 months ago (Nov. 28, 2006)
Published Print	18 years, 9 months ago (Nov. 28, 2006)

Funders 0

None

BibTeX

@article{Andrabi_2006, title={Poly(ADP-ribose) (PAR) polymer is a death signal}, volume={103}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0606526103}, DOI={10.1073/pnas.0606526103}, number={48}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Andrabi, Shaida A. and Kim, No Soo and Yu, Seong-Woon and Wang, Hongmin and Koh, David W. and Sasaki, Masayuki and Klaus, Judith A. and Otsuka, Takashi and Zhang, Zhizheng and Koehler, Raymond C. and Hurn, Patricia D. and Poirier, Guy G. and Dawson, Valina L. and Dawson, Ted M.}, year={2006}, month=nov, pages={18308–18313} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        8,
        31
      ]
    ],
    "date-time": "2025-08-31T10:08:11Z",
    "timestamp": 1756634891421
  },
  "reference-count": 34,
  "publisher": "Proceedings of the National Academy of Sciences",
  "issue": "48",
  "content-domain": {
    "domain": [
      "www.pnas.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        2006,
        11,
        28
      ]
    ]
  },
  "abstract": "<jats:p>Excessive activation of the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP-1) plays a prominent role in various of models of cellular injury. Here, we identify poly(ADP-ribose) (PAR) polymer, a product of PARP-1 activity, as a previously uncharacterized cell death signal. PAR polymer is directly toxic to neurons, and degradation of PAR polymer by poly(ADP-ribose) glycohydrolase (PARG) or phosphodiesterase 1 prevents PAR polymer-induced cell death. PARP-1-dependent, NMDA excitotoxicity of cortical neurons is reduced by neutralizing antibodies to PAR and by overexpression of PARG. Neuronal cultures with reduced levels of PARG are more sensitive to NMDA excitotoxicity than WT cultures. Transgenic mice overexpressing PARG have significantly reduced infarct volumes after focal ischemia. Conversely, mice with reduced levels of PARG have significantly increased infarct volumes after focal ischemia compared with WT littermate controls. These results reveal PAR polymer as a signaling molecule that induces cell death and suggests that interference with PAR polymer signaling may offer innovative therapeutic approaches for the treatment of cellular injury.</jats:p>",
  "DOI": "10.1073/pnas.0606526103",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2006,
        11,
        21
      ]
    ],
    "date-time": "2006-11-21T01:57:31Z",
    "timestamp": 1164074251000
  },
  "page": "18308-18313",
  "update-policy": "http://dx.doi.org/10.1073/pnas.cm10313",
  "source": "Crossref",
  "is-referenced-by-count": 545,
  "title": "Poly(ADP-ribose) (PAR) polymer is a death signal",
  "prefix": "10.1073",
  "volume": "103",
  "author": [
    {
      "given": "Shaida A.",
      "family": "Andrabi",
      "sequence": "first",
      "affiliation": [
        {
          "name": "*Institute for Cell Engineering,"
        },
        {
          "name": "Departments of \u2020Neurology,"
        }
      ]
    },
    {
      "given": "No Soo",
      "family": "Kim",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "*Institute for Cell Engineering,"
        },
        {
          "name": "Departments of \u2020Neurology,"
        }
      ]
    },
    {
      "given": "Seong-Woon",
      "family": "Yu",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "*Institute for Cell Engineering,"
        },
        {
          "name": "Departments of \u2020Neurology,"
        }
      ]
    },
    {
      "given": "Hongmin",
      "family": "Wang",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "*Institute for Cell Engineering,"
        },
        {
          "name": "Departments of \u2020Neurology,"
        }
      ]
    },
    {
      "given": "David W.",
      "family": "Koh",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "*Institute for Cell Engineering,"
        },
        {
          "name": "Departments of \u2020Neurology,"
        }
      ]
    },
    {
      "given": "Masayuki",
      "family": "Sasaki",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "*Institute for Cell Engineering,"
        },
        {
          "name": "Departments of \u2020Neurology,"
        }
      ]
    },
    {
      "given": "Judith A.",
      "family": "Klaus",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and"
        }
      ]
    },
    {
      "given": "Takashi",
      "family": "Otsuka",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and"
        }
      ]
    },
    {
      "given": "Zhizheng",
      "family": "Zhang",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and"
        }
      ]
    },
    {
      "given": "Raymond C.",
      "family": "Koehler",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and"
        }
      ]
    },
    {
      "given": "Patricia D.",
      "family": "Hurn",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and"
        }
      ]
    },
    {
      "given": "Guy G.",
      "family": "Poirier",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "**Health and Environment Unit, Laval University Medical Research Center, Centre Hospitalier Universitaire de Quebec, Ste-Foy, QC, Canada G1V 4G2"
        }
      ]
    },
    {
      "given": "Valina L.",
      "family": "Dawson",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "*Institute for Cell Engineering,"
        },
        {
          "name": "Departments of \u2020Neurology,"
        },
        {
          "name": "Neuroscience,"
        },
        {
          "name": "Physiology, and"
        }
      ]
    },
    {
      "given": "Ted M.",
      "family": "Dawson",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "*Institute for Cell Engineering,"
        },
        {
          "name": "Departments of \u2020Neurology,"
        },
        {
          "name": "Neuroscience,"
        }
      ]
    }
  ],
  "member": "341",
  "published-online": {
    "date-parts": [
      [
        2006,
        11,
        28
      ]
    ]
  },
  "reference": [
    {
      "key": "e_1_3_4_1_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.nbd.2003.08.008"
    },
    {
      "key": "e_1_3_4_2_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0165-6147(98)01193-6"
    },
    {
      "key": "e_1_3_4_3_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0921-8777(00)00016-1"
    },
    {
      "key": "e_1_3_4_4_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0065-2571(99)00024-2"
    },
    {
      "key": "e_1_3_4_5_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1086/302389"
    },
    {
      "key": "e_1_3_4_6_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/BF00928438"
    },
    {
      "key": "e_1_3_4_7_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1023/A:1022316914492"
    },
    {
      "key": "e_1_3_4_8_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/s00018-002-8527-2"
    },
    {
      "key": "e_1_3_4_9_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.272.18.11895"
    },
    {
      "key": "e_1_3_4_10_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1124/pr.54.3.375"
    },
    {
      "key": "e_1_3_4_11_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/nm1097-1089"
    },
    {
      "key": "e_1_3_4_12_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1523/JNEUROSCI.20-21-08005.2000"
    },
    {
      "key": "e_1_3_4_13_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.2307/3576299"
    },
    {
      "key": "e_1_3_4_14_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/294284a0"
    },
    {
      "key": "e_1_3_4_15_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.0406182101"
    },
    {
      "key": "e_1_3_4_16_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.2237114100"
    },
    {
      "key": "e_1_3_4_17_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.96.10.5774"
    },
    {
      "key": "e_1_3_4_18_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.1072221"
    },
    {
      "key": "e_1_3_4_19_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1523/JNEUROSCI.3461-04.2004"
    },
    {
      "key": "e_1_3_4_20_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1523/JNEUROSCI.18-06-02040.1998"
    },
    {
      "key": "e_1_3_4_21_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.M104920200"
    },
    {
      "key": "e_1_3_4_22_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/bi00385a042"
    },
    {
      "key": "e_1_3_4_23_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/abio.1993.1004"
    },
    {
      "key": "e_1_3_4_24_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/excr.1998.4321"
    },
    {
      "key": "e_1_3_4_25_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(19)42597-0"
    },
    {
      "key": "e_1_3_4_26_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.yexcr.2004.03.050"
    },
    {
      "key": "e_1_3_4_27_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1042/BJ20040942"
    },
    {
      "key": "e_1_3_4_28_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/01.STR.0000014203.65693.1E"
    },
    {
      "key": "e_1_3_4_29_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1523/JNEUROSCI.13-06-02651.1993"
    },
    {
      "key": "e_1_3_4_30_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0304-4165(99)00054-9"
    },
    {
      "key": "e_1_3_4_31_2",
      "volume-title": "Current Protocols in Cell Biology",
      "author": "Haince JF",
      "year": "2005",
      "unstructured": "JF Haince, GG Poirier, JB Kirkland Current Protocols in Cell Biology, eds JS Bonifacion, M Dasso, JB Harford, J Lippincott-Schwartz, K Yamada (Wiley, Indianapolis, Unit 18.7. (2005)."
    },
    {
      "key": "e_1_3_4_32_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.4067/S0717-95022003000300006"
    },
    {
      "key": "e_1_3_4_33_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/01.STR.20.1.84"
    },
    {
      "key": "e_1_3_4_34_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/01.STR.0000163083.59201.34"
    }
  ],
  "container-title": "Proceedings of the National Academy of Sciences",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://pnas.org/doi/pdf/10.1073/pnas.0606526103",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2022,
        4,
        12
      ]
    ],
    "date-time": "2022-04-12T19:20:21Z",
    "timestamp": 1649791221000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://pnas.org/doi/full/10.1073/pnas.0606526103"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2006,
        11,
        28
      ]
    ]
  },
  "references-count": 34,
  "journal-issue": {
    "issue": "48",
    "published-print": {
      "date-parts": [
        [
          2006,
          11,
          28
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1073/pnas.0606526103"
  ],
  "URL": "http://dx.doi.org/10.1073/pnas.0606526103",
  "relation": {},
  "ISSN": [
    "0027-8424",
    "1091-6490"
  ],
  "subject": [],
  "container-title-short": "Proc. Natl. Acad. Sci. U.S.A.",
  "published": {
    "date-parts": [
      [
        2006,
        11,
        28
      ]
    ]
  },
  "assertion": [
    {
      "value": "2006-07-31",
      "order": 0,
      "name": "received",
      "label": "Received",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "2006-11-28",
      "order": 2,
      "name": "published",
      "label": "Published",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    }
  ]
}