Linked Life Data

20926829

Source:http://linkedlifedata.com/resource/pubmed/id/20926829

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2010-12-1
pubmed:abstractText
Poly(ADP-ribose) metabolism, mediated mainly by poly(ADP-ribose) polymerase (PARP) 1 and poly(ADP-ribose) glycohydrolase (PARG), regulates various cellular processes in response to genotoxic stress. PARP1 has been shown to be important in multiple cellular processes, including DNA repair, chromosomal stability, chromatin function, apoptosis and transcriptional regulation. However, whether PARP1's polymer synthesizing activity or polymer homeostasis is responsible for these functions remains largely unknown. Given a concerted action of multiple PARPs and unique PARG in the homeostasis of poly(ADP-ribosyl)ation, PARG is hypothesized to function in these processes. The lethal phenotype of the PARG null mutation in mouse embryos, however, hampers further investigation on biological function of PARG. Here, we show that mouse embryonic fibroblasts carrying a hypomorphic mutation of PARG, i.e. lacking the nuclear 110 kD isoform (PARG(110)(-/-)), have defects in the repair of DNA damage caused by various genotoxic agents. PARG(110)(-/-) cells exhibit genomic instability, characterized by a high frequency of sister chromatid exchange, micronuclei formation and chromosomal aberrations. Moreover, mutant cells contain supernumerary centrosomes, another hallmark of genomic instability, which correlates with an accumulation of S-phase cells after replication poison. Intriguingly, PARG(110)(-/-) cells accumulate more Rad51 foci in response to hydroxyurea, indicative of a defective repair of replication fork damage. Finally, PARG(110)(-/-) mice are susceptible to diethylnitrosamine-induced hepatocellular carcinoma. These data demonstrate that the homeostasis of poly(ADP-ribosyl)ation is important for an efficient DNA repair of damaged replication forks and for stabilizing the genome, thereby preventing carcinogenesis.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1460-2180
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
31
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2058-65
pubmed:meshHeading
pubmed-meshheading:20926829-Animals, pubmed-meshheading:20926829-Cell Nucleus, pubmed-meshheading:20926829-Cells, Cultured, pubmed-meshheading:20926829-Chromosome Aberrations, pubmed-meshheading:20926829-DNA Breaks, Double-Stranded, pubmed-meshheading:20926829-DNA Breaks, Single-Stranded, pubmed-meshheading:20926829-DNA Repair, pubmed-meshheading:20926829-DNA Replication, pubmed-meshheading:20926829-Genomic Instability, pubmed-meshheading:20926829-Glycoside Hydrolases, pubmed-meshheading:20926829-Isoenzymes, pubmed-meshheading:20926829-Liver Neoplasms, Experimental, pubmed-meshheading:20926829-Mice, pubmed-meshheading:20926829-Micronuclei, Chromosome-Defective, pubmed-meshheading:20926829-Neoplasms, pubmed-meshheading:20926829-Poly(ADP-ribose) Polymerases, pubmed-meshheading:20926829-Rad51 Recombinase, pubmed-meshheading:20926829-Sister Chromatid Exchange
pubmed:year
2010
pubmed:articleTitle
Deletion of the nuclear isoform of poly(ADP-ribose) glycohydrolase (PARG) reveals its function in DNA repair, genomic stability and tumorigenesis.
pubmed:affiliation
Leibniz Institute for Age Research-Fritz Lipmann Institute (FLI), 07745, Jena, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't