High Resolution Fractionation and Characterization of ADP-Ribose Polymers

Kiehlbauch, Charles C.; Aboul-Ela, Nasreen; Jacobson, Elaine L.; Ringer, David P.; Jacobson, Myron K.

doi:10.1006/abio.1993.1004

Cited by 75 publications

(76 citation statements)

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“…How the polymer branching impacts on these parameters is not known at present. However, in general, branching increases with PAR size [36,37]. We identified PARP-1 as the major configurator of PAR as a cell death signal, while …”

Section: Discussionmentioning

confidence: 83%

The roles of poly(ADP-ribose)-metabolizing enzymes in alkylation-induced cell death

Cohausz

Blenn

Malanga

et al. 2008

Cell. Mol. Life Sci.

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Abstract. Poly(ADP-ribose) (PAR) has been identified as a DNA damage-inducible cell death signal upstream of apoptosis-inducing factor (AIF). PAR causes the translocation of AIF from mitochondria to the nucleus and triggers cell death. In living cells, PAR molecules are subject to dynamic changes pending on internal and external stress factors. Using RNA interference (RNAi), we determined the roles of poly(ADP-ribose) polymerases-1 and -2 (PARP-1, PARP-2) and poly(ADP-ribose) glycohydrolase (PARG), the key enzymes configuring PAR molecules, in cell death induced by an alkylating agent. We found that PARP-1, but not PARP-2 and PARG, contributed to alkylation-induced cell death. Likewise, AIF translocation was only affected by PARP-1. PARP-1 seems to play a major role configuring PAR as a death signal involving AIF translocation regardless of the death pathway involved.

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Section: Discussionmentioning

confidence: 83%

The roles of poly(ADP-ribose)-metabolizing enzymes in alkylation-induced cell death

Cohausz

Blenn

Malanga

et al. 2008

Cell. Mol. Life Sci.

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“…2F) (22). An 80 nM concentration of 16 ADPribose residues causes a small amount of AIF release, whereas 80 nM of polymers of 30 ADP-ribose residues induce modest AIF release and 80 nM of polymers greater then 60 ADP-ribose units or the mixed polymer fraction induce robust AIF release (Fig.…”

Section: Par Polymermentioning

confidence: 88%

“…PAR polymer was synthesized and purified after in vitro automodification of PARP-1 and has a mean length of 40 ADP-ribose residues as determined by HPLC methods and gel electrophoresis (21). The range of size of PAR in this mix is 6-mer through 100-mer ADP-ribose units (21,22). Purified PAR polymer induces AIF release in a manner similar to SN(PAR) (Fig.…”

Section: Par Polymermentioning

confidence: 99%

Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death

Andrabi

Wang

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

664

549

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Apoptosis-inducing factor (AIF), a mitochondrial oxidoreductase, is released into the cytoplasm to induce cell death in response to poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) activation. How PARP-1 activation leads to AIF release is not known. Here we identify PAR polymer as a cell death signal that induces release of AIF. PAR polymer induces mitochondrial AIF release and translocation to the nucleus. PAR glycohydrolase, which degrades PAR polymer, prevents PARP-1-dependent AIF release. Cells with reduced levels of AIF are resistant to PARP-1-dependent cell death and PAR polymer cytotoxicity. These results reveal PAR polymer as an AIF-releasing factor that plays important roles in PARP-1-dependent cell death.excitotoxicity ͉ poly(ADP-ribose) polymerase

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“…The iPOND assay was performed essentially as described 47 Synthesis and fractionation of PAR. PAR was synthesized, purified and HPLC fractionated as described 52,67,68 . Briefly, a reaction mixture containing 150 nM recombinant PARP1 was incubated in 100 mM Tris-HCl pH 7.8, 10 mM MgCl 2 , 10 mM DTT, 60 mg ml À 1 histone H1, 60 mg ml À 1 histone type IIa, 1 mM NAD þ and 50 mg ml À 1 double-stranded activator oligonucleotide 5 0 -GGAATTCC-3 0 for 15 min at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation

et al. 2013

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Damaged replication forks activate poly(ADP-ribose) polymerase 1 (PARP1), which catalyses poly(ADP-ribose) (PAR) formation; however, how PARP1 or poly(ADP-ribosyl)ation is involved in the S-phase checkpoint is unknown. Here we show that PAR, supplied by PARP1, interacts with Chk1 via a novel PAR-binding regulatory (PbR) motif in Chk1, independent of ATR and its activity. iPOND studies reveal that Chk1 associates readily with the unperturbed replication fork and that PAR is required for efficient retention of Chk1 and phosphorylated Chk1 at the fork. A PbR mutation, which disrupts PAR binding, but not the interaction with its partners Claspin or BRCA1, impairs Chk1 and the S-phase checkpoint activation, and mirrors Chk1 knockdown-induced hypersensitivity to fork poisoning. We find that long chains, but not short chains, of PAR stimulate Chk1 kinase activity. Collectively, we disclose a previously unrecognized mechanism of the S-phase checkpoint by PAR metabolism that modulates Chk1 activity at the replication fork.

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High Resolution Fractionation and Characterization of ADP-Ribose Polymers

Cited by 75 publications

References 0 publications

The roles of poly(ADP-ribose)-metabolizing enzymes in alkylation-induced cell death

The roles of poly(ADP-ribose)-metabolizing enzymes in alkylation-induced cell death

Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death

Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation

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