Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cell strain 46BR, derived from an immunodeficient individual, is hypersensitive to the lethal effects of DNA-damaging agents, and of 3-aminobenzamide (3AB), the latter being an inhibitor of the enzyme ADP-ribosyltransferase (ADPRT). This hypersensitivity is not found with the noninhibitory analogue, 3-aminobenzoate. The NAD content of 46BR cells is similar to that of fibroblasts from normal human donors, as is the decrease in NAD content following treatment with dimethylsulphate. Both the activity of ADP-ribosyltransferase and its inhibition by 3AB in permeabilized cells are similar in 46BR and in normal cell strains. High concentrations of 3AB interfere with purine metabolism in cultured cells. Again this effect is similar in 46BR and normal cells. Thus there is no apparent anomaly either in the activity of ADPRT or in the gross effects of 3AB in 46BR. The sensitivity to 3AB may be caused by a defect in a specific acceptor for the ADP-ribose synthesized by ADPRT, or in some as yet undiscovered action of the inhibitor.
Carcinogenesis 1985 Jun
PMID:NAD and the synthesis of (ADP-ribose)n in a human cell strain (46BR) hypersensitive to the lethal effects of 3-aminobenzamide. 298 9

Benzamides are potent inhibitors of nuclear ADP-ribosyltransferase and have been extensively used to demonstrate the involvement of ADP-ribosylation in cellular function. When permeabilized L1210 cells are treated with 50 microM 3-acetylamidobenzamide (3-aab) the enzyme is inhibited. However, when 50 nM 3-aab is used a two-fold stimulation of enzyme activity is produced. This anomalous stimulation is obtained with benzamides and nicotinamides and is correlated with their activity as inhibitors. Strikingly the steady-state level of poly(ADP-ribose) in intact cells is increased by these low levels of inhibitors. The mechanisms of this effect and its consequences for the experimental use of benzamides are discussed.
Carcinogenesis 1988 Nov
PMID:Benzamides can stimulate as well as inhibit the activity of nuclear ADP-ribosyltransferase. 314 Oct 76

Following treatment of human fibroblasts with dimethyl-sulphate, more breaks persisted in DNA in cells incubated with 3-aminobenzamide, an inhibitor of ADP-ribosyltransferase, than in its absence. This effect of 3-aminobenzamide was more pronounced in non-dividing than in dividing cells. If non-dividing cells were treated with dimethylsulphate and then incubated for a few hours in the absence of 3-aminobenzamide, few breaks were detectable in the DNA. Subsequent addition of 3-aminobenzamide resulted in the reappearance of many breaks in the DNA. These data suggest that continued synthesis of poly(ADP-ribose) reduces the steady state level of breaks during excision repair of alkylation damage. This is probably mediated by the stimulation of DNA ligase activity. Inhibition of poly(ADP-ribose) synthesis with 3-aminobenzamide maintains or restores a higher steady-state level of breaks.
Carcinogenesis 1984 Jan
PMID:Poly(ADP-ribosylation) reduces the steady-state level of breaks in DNA following treatment of human cells with alkylating agents. 631 22

During carcinogenesis, cells are exposed to increased replication stress due to replication fork arrest at sites of DNA lesions and difficult to replicate genomic regions. Efficient fork restart and DNA repair are important for cancer cell proliferation. We previously showed that the ADP-ribosyltransferase PARP10 interacts with the replication protein proliferating cell nuclear antigen and promotes lesion bypass by recruiting specialized, non-replicative DNA polymerases. Here, we show that PARP10 is overexpressed in a large proportion of human tumors. To understand the role of PARP10 in cellular transformation, we inactivated PARP10 in HeLa cancer cells by CRISPR/Cas9-mediated gene knockout, and overexpressed it in non-transformed RPE-1 cells. We found that PARP10 promotes cellular proliferation, and its overexpression alleviates cellular sensitivity to replication stress and fosters the restart of stalled replication forks. Importantly, mouse xenograft studies showed that loss of PARP10 reduces the tumorigenesis activity of HeLa cells, while its overexpression results in tumor formation by non-transformed RPE-1 cells. Our findings indicate that PARP10 promotes cellular transformation, potentially by alleviating replication stress and suggest that targeting PARP10 may represent a novel therapeutic approach.
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PMID:PARP10 promotes cellular proliferation and tumorigenesis by alleviating replication stress. 3003 50

The DNA damage response is essential to maintain genomic stability, suppress replication stress, and protect against carcinogenesis. The ATR-CHK1 pathway is an essential component of this response, which regulates cell cycle progression in the face of replication stress. PARP14 is an ADP-ribosyltransferase with multiple roles in transcription, signaling, and DNA repair. To understand the biological functions of PARP14, we catalogued the genetic components that impact cellular viability upon loss of PARP14 by performing an unbiased, comprehensive, genome-wide CRISPR knockout genetic screen in PARP14-deficient cells. We uncovered the ATR-CHK1 pathway as essential for viability of PARP14-deficient cells, and identified regulation of DNA replication dynamics as an important mechanistic contributor to the synthetic lethality observed. Our work shows that PARP14 is an important modulator of the response to ATR-CHK1 pathway inhibitors.
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PMID:Genome-wide CRISPR synthetic lethality screen identifies a role for the ADP-ribosyltransferase PARP14 in DNA replication dynamics controlled by ATR. 3254 89