Altered poly(ADP-ribose) metabolism impairs cellular responses to genotoxic stress in a hypomorphic mutant of poly(ADP-ribose) glycohydrolase.

Altered poly(ADP-ribose) metabolism impairs cellular responses to genotoxic stress in a hypomorphic mutant of poly(ADP-ribose) glycohydrolase. Research Abstract Details 

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Altered poly(ADP-ribose) metabolism impairs cellular responses to genotoxic stress in a hypomorphic mutant of poly(ADP-ribose) glycohydrolase. Abstract Text:

Hong Gao,Donna L Coyle,Mirella L Meyer-Ficca,Ralph G Meyer,Elaine L Jacobson,Zhao-Qi Wang,Myron K Jacobson,

Genotoxic stress activates nuclear poly(ADP-ribose) (PAR) metabolism leading to PAR synthesis catalyzed by DNA damage activated poly(ADP-ribose) polymerases (PARPs) and rapid PAR turnover by action of nuclear poly(ADP-ribose) glycohydrolase (PARG). The involvement of PARP-1 and PARP-2 in responses to DNA damage has been well studied but the involvement of nuclear PARG is less well understood. To gain insights into the function of nuclear PARG in DNA damage responses, we have quantitatively studied PAR metabolism in cells derived from a hypomorphic mutant mouse model in which exons 2 and 3 of the PARG gene have been deleted (PARG-Delta2,3 cells), resulting in a nuclear PARG containing a catalytic domain but lacking the N-terminal region (A domain) of the protein. Following DNA damage induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), we found that the activity of both PARG and PARPs in intact cells is increased in PARG-Delta2,3 cells. The increased PARG activity leads to decreased PARP-1 automodification with resulting increased PARP activity. The degree of PARG activation is greater than PARP, resulting in decreased PAR accumulation. Following MNNG treatment, PARG-Delta2,3 cells show reduced formation of XRCC1 foci, delayed H2AX phosphorylation, decreased DNA break intermediates during repair, and increased cell death. Our results show that a precise coordination of PARPs and PARG activities is important for normal cellular responses to DNA damage and that this coordination is defective in the absence of the PARG A domain.

Altered poly(ADP-ribose) metabolism impairs cellular responses to genotoxic stress in a hypomorphic mutant of poly(ADP-ribose) glycohydrolase. Publishing Authors By Initials

H Gao,DL Coyle,ML Meyer-Ficca,RG Meyer,EL Jacobson,ZQ Wang,MK Jacobson,

For similar natural sciences: time: time factors research abstracts see: natural sciences: time: time factors research

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Altered poly(ADP-ribose) metabolism impairs cellular responses to genotoxic stress in a hypomorphic mutant of poly(ADP-ribose) glycohydrolase. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Experimental cell research

VOLUME: 313

Page Numbers: 984-96

Journal Abbreviation: Exp. Cell Res.

ISSN: 0014-4827

DAY: 10

MONTH: 01

YEAR: 2007

Altered poly(ADP-ribose) metabolism impairs cellular responses to genotoxic stress in a hypomorphic mutant of poly(ADP-ribose) glycohydrolase. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 373226

Altered poly(ADP-ribose) metabolism impairs cellular responses to genotoxic stress in a hypomorphic mutant of poly(ADP-ribose) glycohydrolase. Keywords Mesh Terms:

KEYWORDS: Time Factors

MESH TERMS: metabolism

Chemical & Substance for Abstract: Altered poly(ADP-ribose) metabolism impairs cellular responses to genotoxic stress in a hypomorphic mutant of poly(ADP-ribose) glycohydrolase. Information

Substance Name: poly ADP-ribose glycohydrolase

Registry Number: EC 3.2.1.143

Grant and Affiliation Information for Altered poly(ADP-ribose) metabolism impairs cellular responses to genotoxic stress in a hypomorphic mutant of poly(ADP-ribose) glycohydrolase.

AFFILIATION: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Room 3985 Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 85724, USA.

Country: United States

AGENCY: United States NIEHS

GRANT: ES-6694

ACRONYM: ES

MEDLINETA: Exp Cell Res

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