PARG dysfunction enhances DNA double strand break formation in S-phase after alkylation DNA damage and augments different cell death pathways
Open Access
- 6 June 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 4 (6), e656
- https://doi.org/10.1038/cddis.2013.133
Abstract
Poly(ADP-ribose) glycohydrolase (PARG) is the primary enzyme responsible for the degradation of poly(ADP-ribose). PARG dysfunction sensitizes cells to alkylating agents and induces cell death; however, the details of this effect have not been fully elucidated. Here, we investigated the mechanism by which PARG deficiency leads to cell death in different cell types using methylmethanesulfonate (MMS), an alkylating agent, and Parg−/− mouse ES cells and human cancer cell lines. Parg−/− mouse ES cells showed increased levels of γ-H2AX, a marker of DNA double strand breaks (DSBs), accumulation of poly(ADP-ribose), p53 network activation, and S-phase arrest. Early apoptosis was enhanced in Parg−/− mouse ES cells. Parg−/− ES cells predominantly underwent caspase-dependent apoptosis. PARG was then knocked down in a p53-defective cell line, MIAPaCa2 cells, a human pancreatic cancer cell line. MIAPaCa2 cells were sensitized to MMS by PARG knockdown. Enhanced necrotic cell death was induced in MIAPaCa2 cells after augmenting γ-H2AX levels and S-phase arrest. Taken together, these data suggest that DSB repair defect causing S-phase arrest, but p53 status was not important for sensitization to alkylation DNA damage by PARG dysfunction, whereas the cell death pathway is dependent on the cell type. This study demonstrates that functional inhibition of PARG may be useful for sensitizing at least particular cancer cells to alkylating agents.Keywords
This publication has 42 references indexed in Scilit:
- PARG is recruited to DNA damage sites through poly(ADP-ribose)- and PCNA-dependent mechanismsNucleic Acids Research, 2011
- Defects in DNA Lesion Bypass Lead to Spontaneous Chromosomal Rearrangements and Increased Cell DeathEukaryotic Cell, 2010
- A New Isoquinolinium Derivative, Cadein1, Preferentially Induces Apoptosis in p53-defective Cancer Cells with Functional Mismatch Repair via a p38-dependent Pathway*Published by Elsevier BV ,2010
- Functional Localization of Two Poly(ADP-Ribose)-Degrading Enzymes to the Mitochondrial MatrixMolecular and Cellular Biology, 2008
- Nutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell SurvivalCell, 2007
- Poly(ADP-Ribose) Polymerase 1 Accelerates Single-Strand Break Repair in Concert with Poly(ADP-Ribose) GlycohydrolaseMolecular and Cellular Biology, 2007
- Sequential Activation of Poly(ADP-Ribose) Polymerase 1, Calpains, and Bax Is Essential in Apoptosis-Inducing Factor-Mediated Programmed NecrosisMolecular and Cellular Biology, 2007
- Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell deathProceedings of the National Academy of Sciences of the United States of America, 2006
- Poly(ADP-ribose) (PAR) polymer is a death signalProceedings of the National Academy of Sciences of the United States of America, 2006
- The 39-kDa poly(ADP-ribose) glycohydrolase ARH3 hydrolyzes O- acetyl-ADP-ribose, a product of the Sir2 family of acetyl-histone deacetylasesProceedings of the National Academy of Sciences of the United States of America, 2006