Role of poly(ADP-ribose) polymerase in rapid intracellular acidification induced by alkylating DNA damage

Affar, El Bachir; Shah, Rashmi G.; Dallaire, Annie-Karine; Castonguay, Vincent; Shah, Girish M.

doi:10.1073/pnas.012460399

Cited by 47 publications

(34 citation statements)

References 36 publications

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“…In support of such a role, it is important to recall that, in most instances, pH clamping does not completely prevent cell apoptosis, suggesting that while pH i changes make important contributions, they may not be essential for apoptosis, perhaps having more to do with the kinetics rather than with the triggering phase of apoptosis. The recent paper by Affar et al 34 seems to be in agreement with this point, as these authors show that intracellular acidification, which immediately develops upon alkylating DNA damage (in contrast to apoptosis-associated acidification, which occurs much later at 2-14 h), may be functioning as a negative regulator of apoptotic death in cells with damaged DNA, through a still unknown mechanism. In this context, how does cytosolic acidification facilitate the occurrence of apoptosis?…”

Section: Intracellular Acidification In Apoptosismentioning

confidence: 56%

Alterations of intracellular pH homeostasis in apoptosis: origins and roles

2004

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Intracellular pH (pH i ) has an important role in the maintenance of normal cell function, and hence this parameter has to be tightly controlled within a narrow range, largely through the activity of transporters located at the plasma membrane. These transporters can be modulated by endogenous or exogenous molecules as well as, in some pathological situations, leading to pH i changes that have been implicated in both cell proliferation and cell death. Whereas intracellular alkalinization seems to be a common feature of proliferative processes, the precise role of pH i in apoptosis is still unclear. The present review gathers the most recent advances along with previous data on both the origin and the role of pH i alterations in apoptosis and highlights the major concerns that merit further research in the future. Special attention is given to the possible role played by pH i -regulating transporters.

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Section: Intracellular Acidification In Apoptosismentioning

confidence: 56%

Alterations of intracellular pH homeostasis in apoptosis: origins and roles

2004

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“…These results could also suggest that mitochondrial matrix swelling, observed in many pathological conditions, 7,14,21,22 may be a consequence of cytosol acidification, a phenomenon frequently observed during necrotic cell death. [23][24][25][26][27] The question remains as to what role does matrix configuration play in cells in which depolarization of the inner membrane is not observed prior to cytochrome c release. 28 It will be interesting to see whether mitochondrial structural changes, brought about by other mechanisms such as mitochondrial fission, 29 or tBid-mediated matrix remodeling, 8 will have a role in potential-independent mitochondria reorganization during apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial membrane potential regulates matrix configuration and cytochrome c release during apoptosis

et al. 2003

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During apoptosis, the mitochondrial membrane potential (MMP) decreases, but it is not known how this relates to the apoptotic process. It was recently suggested that cytochrome c is compartmentalized in closed cristal regions and therefore, matrix remodeling is required to attain complete cytochrome c release from the mitochondria. In this work we show that, at the onset of apoptosis, changes in MMP control matrix remodeling prior to cytochrome c release. Early after growth factor withdrawal the MMP declines and the matrix condenses. Both phenomena are reversed by adding oxidizable substrates. In mitochondria isolated from healthy cells, matrix condensation can be induced by either denying oxidizable substrates or by protonophores that dissipate the membrane potential. Matrix remodeling to the condensed state results in cristal unfolding and exposes cytochrome c to the intermembrane space facilitating its release from the mitochondria during apoptosis. In contrast, when a transmembrane potential is generated due to either electron transport or a pH gradient formed by acidifying the medium, mitochondria maintain an orthodox configuration in which most cytochrome c is sequestered in the cristae and is resistant to release by agents that disrupt the mitochondrial outer membrane.

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“…The cell extracts were prepared and resolved on 8% SDS-PAGE, followed by transfer to nitrocellulose and immunoblotting as described previously (Affar et al, 2002;Shah et al, 1995b). The specific antibodies used were: anti-PARP monoclonal (C-2-10, Aparptosis, 1:10,000) or anti-pADPr monoclonal 10H (Kawamitsu et al, 1984) (1:100) or anti-pADPr polyclonal LP96-10 (Aparptosis, 1:10,000) and anti-β-actin monoclonal (Sigma, 1:20,000).…”

Section: Western Blotmentioning

confidence: 99%

Mechanism of early biphasic activation of poly(ADP-ribose) polymerase-1 in response to ultraviolet B radiation

Vodenicharov

Ghodgaonkar

Halappanavar

et al. 2005

Journal of Cell Science

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The damage to DNA caused by ultraviolet B radiation (280-320 nm) contributes significantly to development of sunlight-induced skin cancers. The susceptibility of mice to ultraviolet B-induced skin carcinogenesis is increased by an inhibitor of the DNA damage-activated nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP), hence PARP activation is likely to be associated with cellular responses that suppress carcinogenesis. To understand the role of activated PARP in these cellular functions, we need to first clearly identify the cause of PARP activation in ultraviolet B-irradiated cells. Ultraviolet B, like ultraviolet C, causes direct DNA damage of cyclobutane pyrimidine dimer and 6, 4-photoproduct types, which are subjected to the nucleotide excision repair. Moreover, ultraviolet B also causes oxidative DNA damage, which is subjected to base excision repair. To identify which of these two types of DNA damage activates PARP, we examined mechanism of early PARP activation in mouse fibroblasts exposed to ultraviolet B and C radiations. The ultraviolet B-irradiated cells rapidly activated PARP in two distinct phases, initially within the first 5 minutes and later between 60-120 minutes, whereas ultraviolet C-irradiated cells showed only the immediate PARP activation. Using antioxidants, local irradiation, chromatin immunoprecipitation and in vitro PARP assays, we identified that ultraviolet radiation-induced direct DNA damage, such as thymine dimers, cause the initial PARP activation, whereas ultraviolet B-induced oxidative damage cause the second PARP activation. Our results suggest that cells can selectively activate PARP for participation in different cellular responses associated with different DNA lesions.

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Role of poly(ADP-ribose) polymerase in rapid intracellular acidification induced by alkylating DNA damage

Cited by 47 publications

References 36 publications

Alterations of intracellular pH homeostasis in apoptosis: origins and roles

Alterations of intracellular pH homeostasis in apoptosis: origins and roles

Mitochondrial membrane potential regulates matrix configuration and cytochrome c release during apoptosis

Mechanism of early biphasic activation of poly(ADP-ribose) polymerase-1 in response to ultraviolet B radiation

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