Journal Article

Deletion of the nuclear isoform of poly(ADP-ribose) glycohydrolase (PARG) reveals its function in DNA repair, genomic stability and tumorigenesis

WooKee Min, Ulrich Cortes, Zdenko Herceg, Wei-Min Tong and Zhao-Qi Wang

in Carcinogenesis

Volume 31, issue 12, pages 2058-2065
Published in print December 2010 | ISSN: 0143-3334
Published online October 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq205
Deletion of the nuclear isoform of poly(ADP-ribose) glycohydrolase (PARG) reveals its function in DNA repair, genomic stability and tumorigenesis

More Like This

Show all results sharing this subject:

  • Clinical Cytogenetics and Molecular Genetics

GO

Show Summary Details

Preview

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 (PARG110−/−), have defects in the repair of DNA damage caused by various genotoxic agents. PARG110−/− 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, PARG110−/− cells accumulate more Rad51 foci in response to hydroxyurea, indicative of a defective repair of replication fork damage. Finally, PARG110−/− 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.

Journal Article.  5814 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.