Both pathways activate caspases, a class of endoproteases that hydrolyze peptide bonds Thornberry and Lazebnik, Although there are various types of caspases, those involved in apoptosis can be classified into two groups, the initiator or apical caspases and the effector or executioner caspases. Initiator caspases e. Upon binding to their cognate ligand, these receptors recruit an adaptor protein Fas-associated death domain FADD that binds and dimerizes the initiator procaspase-8, to form an oligomeric death-inducing signaling complex DISC , in which procaspase-8 becomes activated through an autoproteolytic cleavage event.
The active caspase-8 then cleaves and activates the effector caspases 3 and 7 Ashkenazi and Dixit, ; Krammer et al. The intrinsic pathway causes mitochondrial outer membrane permeabilization MOMP , which leads to release of cytochrome c , a mitochondrial protein which transfers electrons from complex III to complex IV in the electron transport chain Wang, The discovery of the role of cytochrome c in apoptosis by Liu et al. In the cytosol, cytochrome c interacts with the apoptotic protease activating factor-1 APAF-1 to form the apoptosome complex Zou et al.
The complex recruits procaspase-9, which converts to active caspase-9 by autocatalysis. Active caspase-9 activates effector caspases like caspase-7 and caspase-3 and causes apoptosis Figure 3. They observed that treatment of mammalian S extracts with RNase strongly increased cytochrome c- induced caspase-9 activation, while the addition of RNA to the extracts impaired caspase-9 activation.
These results implicated an inhibitory role of RNA in the activation of caspase Systematic evaluation of the steps leading to caspase-9 activation identified cytochrome c as the target of the RNA inhibitor. Analysis of cytochrome c -associated species revealed that tRNA binds specifically to cytochrome c. Microinjection of tRNA into living cells inhibited the ability of cytochrome c to induce apoptosis, while degradation of tRNA by an RNase that preferentially degrades tRNA, onconase, enhanced apoptosis via the intrinsic pathway.
Taken together, these findings showed that tRNA binds to cytochrome c and inhibits formation of the apoptosome Mei et al. This suggested a direct role for tRNA in regulating apoptosis and revealed an intimate connection between translation and cell death. This finding also raised an interesting question as to how the interaction between tRNA and cytochrome c modulates apoptosis. This question was addressed recently by Gorla et al.
This model was further confirmed by the observation that cytochrome c lost its ability to interact with tRNA after treatment with oxidizing agents or cysteine modifying agents. Hence tRNA can regulate apoptosis by binding to cytochrome c. Further investigation of the nucleotide residues of tRNA involved in these interactions is required to answer questions about how tRNA binding to cytochrome c is regulated in the cell, whether specific tRNA isoacceptors are involved, and if this interaction is non-specific.
Increased expression of tRNA has been detected in a wide variety of transformed cells Marshall and White, , such as ovarian and cervical cancer Winter et al. Expression levels of tRNA molecules in breast cancer cells were fold higher as compared to in normal cells and overexpression of tRNA i Met induces proliferation and immortalization of fibroblasts and also significantly alters the global tRNA expression profile Pavon-Eternod et al.
It was also observed that certain individual tRNAs were overexpressed more as compared to others. Identification of the tRNA sites involved in binding to cytochrome c might help elucidate the connection between tRNA overexpression and cancer.
While aa-tRNAs have been implicated in variety of roles in biosynthetic pathways, much less is known about the various functions of uncharged tRNAs in cells apart from their role in acting as sensors for cellular stress like nutritional deprivation. The recent discovery of the role of tRNA in regulating apoptosis has opened a whole new field which requires investigation into tRNA-protein interactions and has created a link between regulation of cell death and cellular metabolism.
With the advent of high throughput sequencing techniques, studying the whole transcriptome of various organisms has become feasible. It is now clear that almost all of the DNA in the cell is transcribed; however, only a small portion of these transcripts are translated into proteins or used as substrates for biological processes. The emergence of these sequencing techniques has resulted in discoveries of novel ncRNAs, and several studies have highlighted their role as important regulators of gene expression.
Among the ncRNAs discovered, a number of cleavage products of tRNAs formed in response to stress have been also been discovered. These cleavage products were initially thought to be a result of random degradation; however, a number of studies have revealed their production to be a result of specific cleavage, and possibly regulated. Although a number of cleavage products have been observed, all the possible mechanisms of their production are not fully understood.
Also regulation of tRNA fragment production, i. A recent study by Hanada et al. This suggests that tRNA cleavage activates apoptosis via activation of p53 and hence protects against cancer, while full-length tRNA binds cytochrome c and prevents apoptosis thereby aiding cancer development.
This hypothesis is strengthened by the overexpression of tRNAs observed in cancer cell lines. Further investigation into the link between tRNA cleavage and p53 activation is required to help understand how tRNAs help regulate the progression of cancer. While their role in tRNA structure stability and translation is well studied, these modifications might aid in the regulation of tRNA fragmentation. Further studies are needed to answer why some tRNAs are cleaved and others not — for example could modifications make certain positions in tRNA more sensitive to RNases or could they be responsible for blocking RNases?
Also, modifications might also help regulate tRNA binding to cytochrome c during apoptosis. Regulation of this interaction and its role in metabolism and tumorigenesis will help our understanding of regulation of death in both normal and cancer cells.
Cells have various mechanisms to sense the absence of a modification and remove non-functional tRNAs Phizicky and Alfonzo, Variations in the modification status of tRNAs during stress have been implicated directly in decoding Dedon and Begley, , and such effects may be accentuated by indirect effects on the generation of regulatory tRFs.
Clearly, much still remains to be discovered about the various regulatory roles of both charged and uncharged tRNA. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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