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)

Breast cancer is one of the leading causes of death worldwide, and therefore, new and improved approaches for the treatment of breast cancer are desperately needed. CtIP (RBBP8) is a multifunctional protein that is involved in various cellular functions, including transcription, DNA replication, DNA repair and the G1 and G2 cell cycle checkpoints. CtIP plays an important role in homologous recombination repair by interacting with tumor suppressor protein BRCA1. Here, we analyzed the expression profile of CtIP by data mining using published microarray data sets. We found that CtIP expression is frequently decreased in breast cancer patients, and the patient group with low-expressing CtIP mRNA is associated with a significantly lower survival rate. The knockdown of CtIP in breast cancer MCF7 cells reduced Rad51 foci numbers and enhanced f H2AX foci formation after f-irradiation, suggesting that deficiency of CtIP decreases homologous recombination repair and delays DNA double strand break repair. To explore the effect of CtIP on PARP inhibitor therapy for breast cancer, CtIP-depleted MCF7 cells were treated with PARP inhibitor olaparib (AZD2281) or veliparib (ABT-888). As in BRCA mutated cells, PARP inhibitors showed cytotoxicity to CtIP-depleted cells by preventing cells from repairing DNA damage, leading to decreased cell viability. Further, a xenograft tumor model in mice with MCF7 cells demonstrated significantly increased sensitivity towards PARP inhibition under CtIP deficiency. In summary, this study shows that low level of CtIP expression is associated with poor prognosis in breast cancer, and provides a rationale for establishing CtIP expression as a biomarker of PARP inhibitor response, and consequently offers novel therapeutic options for a significant subset of patients.
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PMID:Loss of CtIP disturbs homologous recombination repair and sensitizes breast cancer cells to PARP inhibitors. 2671 4

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

RNA processing was recently found to affect DNA damage response. The RNA processing factors THRAP3 and BCLAF1 play critical role in keeping DNA genomic stability by regulating the transcription, mRNA splicing and export of DNA repair proteins BRCA2, PALB2, Rad51, FANCD2, and FANCL in response to DNA damage. RNA processing factors THRAP3 and BCLAF1 play critical roles in maintaining DNA genomic stability. These factors regulate transcription, mRNA splicing and nuclear RNA export of DNA repair proteins BRCA2, PALB2, Rad51, FANCD2, and FANCL in response to DNA damage. Splicing factors SRSF10 and Sam68 were found to control the DNA damage agent-induced mRNA splicing of transcripts including BCLAF1, BRCA1, BCL2L1, CASP8, CHK2, and RBBP8 to regulate apoptosis, cell-cycle transition and DNA repair. Splicing factors and RNA binding proteins (RBPs) were also found to play a critical role in DNA/RNA hybrids (R-loops) formed during transcription and RNA processing to prevent RNA-induced genome instability. At the same time, DNA repair proteins FANCI and FANCD2 were found to regulate the nuclear localization of splicing factors SF3B1 in the DNA damage response. In addition, tumor-derived extracellular vesicles (Evs) enhanced by chemotherapeutic agents in cancer were found to promote cancer metastasis and drug resistance. Inhibiting Evs from cancer cells significantly reduced cancer metastasis and drug resistance. Furthermore, cross-talk between the DNA damage response and the immune response was observed including the enhancement of the efficacy of immune checkpoint blockade by PARP inhibitors and the effect of PD-L1 on mRNA stability of various mRNAs involved in DNA damage response by acting as a novel RNA binding protein to increase drug resistance in cancer cells. This review will introduce recent progress on the interplay of the DNA damage response, the RNA processing and the extracellular vesicles mediated metastasis.
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PMID:The Interplay Between the DNA Damage Response, RNA Processing and Extracellular Vesicles. 3201 Jun 26