Abstract
Gadd45 genes have been implicated in stress signaling in response to physiological or environmental stressors, which results in cell cycle arrest, DNA repair, cell survival and senescence, or apoptosis. Evidence accumulated implies that Gadd45 proteins function as stress sensors is mediated by a complex interplay of physical interactions with other cellular proteins that are implicated in cell cycle regulation and the response of cells to stress. These include PCNA, p21, cdc2/cyclinB1, and the p38 and JNK stress response kinases. What deterministic factors dictate whether Gadd45 and partner proteins function in either cell survival or apoptosis remains to be determined. An attractive working model to consider is that the extent of cellular/DNA damage, in a given cell type, dictates the association of different Gadd45 proteins with particular partner proteins, which determines the outcome.
Highlights
The cellular response to stress The cellular response to environmental and physiological stress is very complex, encompassing a myriad of molecular pathways, with a plethora of regulators and effectors
X-rays damage DNA primarily by generating hydroxyl radicals, produced by oxidative stress, which alter the structure of bases, and the resulting DNA damage is repaired by various base-excision repair mechanisms [1]
Gadd45 genes have been implicated in stress signaling, which results in cell cycle arrest, DNA repair and cell survival, or apoptosis (Fig. 2)
Summary
The cellular response to stress The cellular response to environmental and physiological stress is very complex, encompassing a myriad of molecular pathways, with a plethora of regulators and effectors. Lesions caused by UV radiation are primarily cyclobutane pyrimidine dimers & 6-4 photoproducts that are repaired by nucleotide-excision repair [1] Alkylating agents, such as methyl methanesulfonate (MMS), represent a major class of chemical agents that damage DNA [3]. Mammalian cells have evolved an elaborate defense mechanism to maintain genomic integrity by preventing the fixation of permanent damage from genotoxic stress This includes activation of cell cycle arrest checkpoints at the G1/S and G2/M transitions [12,13,14] and activation of a cell death program [9,10]. The molecular/genetic circuitries of stress response pathways and their mode of action have not yet been fully delineated How such pathways interact to signal either cell cycle arrest or programmed cell death is still not clearly understood.
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