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Poly(ADP-ribose) Polymerase Mediates the Suicide Response to Massive DNA Damage: Studies in Normal and DNA-repair Defective Cells
| Content Provider | Scilit |
|---|---|
| Author | Berger, N. A. Sims, J. L. Catino, D. M. Berger, S. J. |
| Copyright Year | 2020 |
| Description | Book Name: ADP-Ribosylation, DNA Repair and Cancer |
| Abstract | Treatment of cells with DNA damaging agents results in a dose dependent decrease in $NAD^{+}$ and ATP pool sizes. The decrease in $NAD^{+}$ is associated with the activation of poly(ADP-ribose) polymerase and the decrease in ATP is consequent to the fall in $NAD^{1+}$. Depletion of both $NAD^{+}$ and ATP can be blocked or retarded by inhibitors of poly(ADP-ribose) polymerase. Both the stimulation of poly(ADP-ribose) synthesis and the effect of enzyme inhibitors have been confirmed in intact cells by using enzymatic cycling techniques to measure the disappearance of $NAD^{+}$ and high pressure liquid chromatography (HPLC) to measure fluctuations in polymer levels. As a consequence of the depletion of $NAD^{+}$ and ATP pools, cells exhibit a marked impairment in their ability to conduct all energy dependent functions. Thus cells treated with high levels of DNA damaging agents exhibit severe suppression of DNA replication and repair, RNA synthesis and protein synthesis. The use of inhibitors of poly-(ADP-ribose) polymerase to prevent the depletion of $NAD^{+}$ and ATP partially restores the cells’ ability to conduct DNA, RNA, and protein synthesis. This preservation of the $NAD^{+}$ and ATP pools accounts for the recent observations that inhibitors of poly(ADP-ribose) stimulate the level of DNA repair synthesis in cells treated with high levels of DNA damaging agents. We have also examined cells from patients with several of the disorders of DNA repair and have found that cells from patients with Fanconi’s anemia have lower than normal $NAD^{+}$ levels. When cells from these patients are treated with DNA damaging agents their $NAD^{+}$ pools are depleted to levels that are lower than those which occur in cells from normal donors. An impaired ability to maintain nucleotide pools and energy dependent functions may contribute to the decreased survival that Fanconi’s anemia cells exhibit following DNA damage. Thus in eukaryotes, high levels of DNA damage activate poly(ADP-ribose) polymerase to a degree that depletes cellular $NAD^{+}$ levels and subsequently depletes ATP levels causing a decrease in energy dependent functions which can consequently lead to cell death before DNA repair can be accomplished. Such a suicide mechanism may be of benefit to an organism where it would be preferrable for cells with severely damaged DNA to die rather than risk repair with a high level of infidelity. |
| Related Links | https://content.taylorfrancis.com/books/download?dac=C2012-0-01963-4&isbn=9781003079491&doi=10.1201/9781003079491-24&format=pdf |
| Ending Page | 226 |
| Page Count | 8 |
| Starting Page | 219 |
| DOI | 10.1201/9781003079491-24 |
| Language | English |
| Publisher | Informa UK Limited |
| Publisher Date | 2020-07-26 |
| Access Restriction | Open |
| Subject Keyword | Book Name: Adp-ribosylation, Dna Repair and Cancer Functions Nad Cell Death Activate Poly Adp Ribose Depletion Suicide Dna Damaging Impaired Ability |
| Content Type | Text |
| Resource Type | Chapter |
