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)

Three mammalian genes encoding DNA ligases--LIG1, LIG3, and LIG4--have been identified. Genetic, biochemical, and cell biology studies indicate that the products of each of these genes play a unique role in mammalian DNA metabolism. Interestingly, cell lines deficient in either DNA ligase I (46BR.1G1) or DNA ligase III (EM9) are sensitive to simple alkylating agents. One interpretation of these observations is that DNA ligases I and III participate in functionally distinct base excision repair (BER) subpathways. In support of this idea, extracts from both DNA ligase-deficient cell lines are defective in catalyzing BER in vitro and both DNA ligases interact with other BER proteins. DNA ligase I interacts directly with proliferating cell nuclear antigen (PCNA) and DNA polymerase beta (Pol beta), linking this enzyme with both short-patch and long-patch BER. In somatic cells, DNA ligase III alpha forms a stable complex with the DNA repair protein Xrcc1. Although Xrcc1 has no catalytic activity, it also interacts with Pol beta and poly(ADP-ribose) polymerase (PARP), linking DNA ligase III alpha with BER and single-strand break repair, respectively. Biochemical studies suggest that the majority of short-patch base excision repair events are completed by the DNA ligase III alpha/Xrcc1 complex. Although there is compelling evidence for the participation of PARP in the repair of DNA single-strand breaks, the role of PARP in BER has not been established.
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PMID:Completion of base excision repair by mammalian DNA ligases. 1155 94

Defective DNA repair has been reported to be a risk factor for various malignancies. Genetic polymorphisms of DNA repair genes are thought to result in different phenotypic features compared to the wild type. Genetic polymorphisms in XRCC1 gene could, through alteration of protein structure, lead to defective functioning of DNA Polbeta, PARP and LIG3 enzymes resulting in defective DNA repair and increased risk of childhood acute lymphoblastic leukemia (ALL). The role of DNA repair gene XRCC1 in susceptibility to childhood ALL has, however, not been widely studied and no data exists from Indian children. In this pilot study, through the use of PCR and RFLP, further confirmed by DNA sequencing, we have shown an increased risk of ALL among children with XRCC1 codons 194 and 399 variant genotypes. Among the three variants, only the association between codon 399 variant and risk of ALL appeared to be significant. The risk of ALL was higher in males with codons 194 and 399 polymorphisms than in females. However, no relation was found between the presence of these variant genotypes and treatment outcome.
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PMID:DNA repair gene XRCC1 polymorphisms in childhood acute lymphoblastic leukemia. 1559 92

Classical non-homologous end-joining (cNHEJ) is the main pathway for the repair of DNA double strand breaks (DSBs) in mammalian cells. In the absence of c-NHEJ, an alternative end-joining (A-EJ) mechanism resolves DSBs. To date, no A-EJ specific factor has been identified. Instead, this mechanism appears to co-opt proteins involved in more than one DNA repair pathway. These include components of base-excision repair (PARP1/XRCC1/LIG3), interstrand cross-link repair (BRCA1/FANCD2), and DSB response/DNA end-resection (MRE11A/RAD50/RBBP8). To clarify the contribution of these factors to A-EJ, here we examined their expression and recruitment to DSBs in correlation with surrogates of cNHEJ (53BP1) and homologous recombination (RAD51) in cells deficient for the cNHEJ end-ligation component XRCC4. This revealed XRCC4-deficient cells exhibited marked increases in the stability of A-EJ transcripts that result in correspondingly elevated levels of associated proteins, in comparison to WT cells. RAD51 was also increased while 53BP1 was unaffected. Treatment with radiomimetic DSB-inducing drug doxorubicin did not influence these activities. However, FANCD2, BRCA1 and XRCC1 foci, prominently associated with 53BP1 foci and hence DSBs resolved by cNHEJ, were only detected in doxorubicin-treated XRCC4-deficient cells. Strikingly, treatment of XRCC4-deficient cells with the PARP-specific inhibitor Niraparib enhanced A-EJ, and substantially induced 53BP1 transcripts and the numbers of A-EJ-associated 53BP1 DNA damage foci. RAD51 was severely inhibited, and upstream cNHEJ (KU70/KU80/DNA-PKCs/ARTEMIS) transcripts were substantially induced. These latter results were recapitulated in BRCA1-deficient cells, which contrastingly did not affect 53BP1 or PARP1 status irrespective of doxorubicin or Niraparib treatment. Hence A-EJ is regulated transcriptionally, reduced by a higher turnover rate in cNHEJ-proficient cells and sustained but fine-tuned by PARP1 in XRCC4-deficient cells to promote DNA repair and survival. Upstream cNHEJ components are similarly transcriptionally down-modulated by PARP1 and BRCA1 in a manner inversely correlated with HR and mechanistically distinct from A-EJ respectively in cNHEJ-deficient and cNHEJ-proficient settings.
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PMID:Regulation of DNA repair in the absence of classical non-homologous end joining. 2992 45

Multiple Myeloma (MM) is a hematologic malignancy strongly characterized by genomic instability, which promotes disease progression and drug resistance. Since we previously demonstrated that LIG3-dependent repair is involved in the genomic instability, drug resistance and survival of MM cells, we here investigated the biological relevance of PARP1, a driver component of Alternative-Non Homologous End Joining (Alt-NHEJ) pathway, in MM. We found a significant correlation between higher PARP1 mRNA expression and poor prognosis of MM patients. PARP1 knockdown or its pharmacological inhibition by Olaparib impaired MM cells viability in vitro and was effective against in vivo xenografts of human MM. Anti-proliferative effects induced by PARP1-inhibition were correlated to increase of DNA double-strand breaks, activation of DNA Damage Response (DDR) and finally apoptosis. Importantly, by comparing a gene expression signature of PARP inhibitors (PARPi) sensitivity to our plasma cell dyscrasia (PC) gene expression profiling (GEP), we identified a subset of MM patients which could benefit from PARP inhibitors. In particular, Gene Set Enrichment Analysis (GSEA) suggested that high MYC expression correlates to PARPi sensitivity in MM. Indeed, we identified MYC as promoter of PARP1-mediated repair in MM and, consistently, we demonstrate that cytotoxic effects induced by PARP inhibition are mostly detectable on MYC-proficient MM cells. Taken together, our findings indicate that MYC-driven MM cells are addicted to PARP1 Alt-NHEJ repair, which represents therefore a druggable target in this still incurable disease.
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PMID:Exploiting MYC-induced PARPness to target genomic instability in multiple myeloma. 3207 92

DNA breaks recruit and activate PARP1/2, which deposit poly-ADP-ribose (PAR) to recruit XRCC1-Ligase3 and other repair factors to promote DNA repair. Clinical PARP inhibitors (PARPi) extend the lifetime of damage-induced PARP1/2 foci, referred to as 'trapping'. To understand the molecular nature of 'trapping' in cells, we employed quantitative live-cell imaging and fluorescence recovery after photo-bleaching. Unexpectedly, we found that PARP1 exchanges rapidly at DNA damage sites even in the presence of clinical PARPi, suggesting the persistent foci are not caused by physical stalling. Loss of Xrcc1, a major downstream effector of PAR, also caused persistent PARP1 foci without affecting PARP1 exchange. Thus, we propose that the persistent PARP1 foci are formed by different PARP1 molecules that are continuously recruited to and exchanging at DNA lesions due to attenuated XRCC1-LIG3 recruitment and delayed DNA repair. Moreover, mutation analyses of the NAD+ interacting residues of PARP1 showed that PARP1 can be physically trapped at DNA damage sites, and identified H862 as a potential regulator for PARP1 exchange. PARP1-H862D, but not PARylation-deficient PARP1-E988K, formed stable PARP1 foci upon activation. Together, these findings uncovered the nature of persistent PARP1 foci and identified NAD+ interacting residues involved in the PARP1 exchange.
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PMID:Clinical PARP inhibitors do not abrogate PARP1 exchange at DNA damage sites in vivo. 3289 Apr 2