DNA damage response pathways in cancer chemotherapy: Investigating roles of PARP and PP2A. Dara Ditsworth

ISBN: 9781109010190

Published:

NOOKstudy eTextbook

254 pages


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DNA damage response pathways in cancer chemotherapy: Investigating roles of PARP and PP2A.  by  Dara Ditsworth

DNA damage response pathways in cancer chemotherapy: Investigating roles of PARP and PP2A. by Dara Ditsworth
| NOOKstudy eTextbook | PDF, EPUB, FB2, DjVu, audiobook, mp3, ZIP | 254 pages | ISBN: 9781109010190 | 8.65 Mb

The deregulation of DNA damage repair and cell death pathways is associated with the development of human cancer and resistance to anti-cancer therapy. The ultimate goal of cancer therapy is to selectively induce cell death and overcome drugMoreThe deregulation of DNA damage repair and cell death pathways is associated with the development of human cancer and resistance to anti-cancer therapy. The ultimate goal of cancer therapy is to selectively induce cell death and overcome drug resistance. We investigated mechanisms of cell death after chemotherapy in cells lacking the ability to undergo apoptosis.

Both in vitro and in tumor xenograft models, DNA alkylating agents induce a program of necrotic cell death that is regulated by the DNA repair enzyme poly(ADP)-ribose polymerase (PARP). Activation of PARP consumes nuclear-cytosolic NAD, induces relocalization of pro-inflammatory nuclear proteins, and ultimately results in cell death that invokes an innate immune response important for tumor clearance. Necrosis in response to DNA alkylating damage is also determined by the metabolic state of the cell, as PARP activation does not induce death in vegetative cells.

Since most cancer cells maintain their ATP production through aerobic glycolysis and are highly sensitive to ATP depletion upon PARP activation, this data might explain why DNA alkylating agents can selectively induce tumor cell death independent of p53 or Bc1-2 family proteins.-In contrast, cell survival following DNA damage involves phosphorylation signaling cascades that enforce a cell-cycle checkpoint until DNA repair processes are complete.

Very little is understood about the role of protein phosphatases in terminating this cascade and promoting cell survival after stress. The activation, target specificity, and subcellular localization of protein phosphatases are thought to be regulated by their binding partners. We investigated the role of the protein phosphatase 2A (PP2A)---associated protein alpha4 in the DNA damage response.

Rather than serve as a specificity factor, we found that alpha4 regulates global PP2A activity. alpha4 plays an essential role in the assembly and maintenance of functional PP2A complexes, and is an important component in the ability of PP2A to form adaptive complexes in response to cellular stress. Taken together, these studies provide insights into our understanding of molecular mediators of necrosis, such as PARP, or cell survival, such as PP2A, and their potential roles in the response to cancer chemotherapy.



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