Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In aerobically growing cells, the guanine base of RNA is oxidized to 8-oxo-7,8-dihydroguanine (8-oxoG), which induces alteration in their gene expression. We previously demonstrated that the human AUF1 protein binds to 8-oxoG in RNA to induce the selective degradation of oxidized messenger RNA. We herein report that the poly(C)-binding protein PCBP1 binds to more severely oxidized RNA to activate apoptosis-related reactions. While AUF1 binds to oligoribonucleotides carrying a single 8-oxoG, PCBP1 does not bind to such oligoribonucleotides but instead binds firmly to oligoribonucleotides in which two 8-oxoG residues are located nearby. PCBP1-deficient cells, constructed from the human HeLa S3 line using the CRISPR-Cas9 system, exhibited higher survival rates than HeLa S3 cells when small doses of hydrogen peroxide were applied. The levels of caspase-3 activation and PARP-1 cleavage in the PCBP1-deficient cells were significantly lower than those in wild-type cells. The structure-function relationship of PCBP1 was established with the use of PCBP1 mutant proteins in which the conserved KH domains were defective. Human cells appear to possess two distinct mechanisms, one controlled by AUF1 and the other by PCBP1, with the former functioning when messenger RNA is moderately oxidized and the latter operating when the RNA is more severely damaged.
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PMID:Specific binding of PCBP1 to heavily oxidized RNA to induce cell death. 2989 75

PCBP1, a member of the poly(C)-binding protein (PCBP) family, has the capability of binding heavily oxidized RNA and therefore participates in the cellular response to oxidative conditions, helping to induce apoptosis. There are four other members of this family, PCBP2, PCBP3, PCBP4, and hnRNPK, but it is not known whether they play similar roles. To learn more, we first tested their affinity for an RNA strand carrying two 8-oxoguanine (8-oxoG) residues at sites located in close proximity to each other, representative of a heavily oxidized strand or RNA with one 8-oxoG or none. Among them, only PCBP2 exhibited highly selective binding to RNA carrying two 8-oxoG residues similar to that observed with PCBP1. In contrast, PCBP3, PCBP4, and hnRNPK bound RNA with or without 8-oxoG modifications and exhibited slightly increased binding to the former. Mutations in conserved RNA-binding domains of PCBP2 disrupted the specific interaction with heavily oxidized RNA. We next tested PCBP2 activity in cells. Compared with WT HeLa S3 cells, PCBP2-KO cells established by gene editing exhibited increased apoptosis with increased caspase-3 activity and PARP1 cleavage under oxidative conditions, which were suppressed by the expression of WT PCBP2 but not one of the mutants lacking binding activity. In contrast, PCBP1-KO cells exhibited reduced apoptosis with much less caspase-3 activity and PARP cleavage than WT cells. Our results indicate that PCBP2 as well as PCBP1 bind heavily oxidized RNA; however, the former may counteract PCBP1 to suppress apoptosis under oxidative conditions.
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PMID:PCBP1 and PCBP2 both bind heavily oxidized RNA but cause opposing outcomes, suppressing or increasing apoptosis under oxidative conditions. 3264 12