A global investigation of gene deletion strains that affect premature stop codon bypass in yeast, Saccharomyces cerevisiae

Samanfar, Bahram; Tan, Le Hoa; Shostak, Kristina; Chalabian, F; Wu, Zongbin; Alamgir,; Sunba, Noor; Burnside, Daniel; Omidi, Katayoun; Hooshyar, M. A.; Márquez, Imelda Galván; Jessulat, Matthew; Smith, Myron L.; Babu, Mohan; Azizi, Ali; Golshani, Ashkan

doi:10.1039/c3mb70501c

Cited by 37 publications

(50 citation statements)

References 37 publications

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“…Besides its role in mRNA translation revealed by our group (6) and others (39), OLA1 has been implicated in DNA damage response (8), oxidative response (9), cell adhesion (40), and heat shock (13). In one recent report, OLA1 has been shown to localize not only in cytoplasm but also in the centrosome and spindle poles.…”

Section: Discussionmentioning

confidence: 87%

OLA1, a Translational Regulator of p21, Maintains Optimal Cell Proliferation Necessary for Developmental Progression

Ding

Liu

Rubio

et al. 2016

Molecular and Cellular Biology

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c OLA1, an Obg-family GTPase, has been implicated in eukaryotic initiation factor 2 (eIF2)-mediated translational control, but its physiological functions remain obscure. Here we report that mouse embryos lacking OLA1 have stunted growth, delayed development leading to immature organs-especially lungs-at birth, and frequent perinatal lethality. Proliferation of primary Ola1 ؊/؊ mouse embryonic fibroblasts (MEFs) is impaired due to defective cell cycle progression, associated with reduced cyclins D1 and E1, attenuated Rb phosphorylation, and increased p21 Cip1/Waf1 . Accumulation of p21 in Ola1 ؊/؊ MEFs is due to enhanced mRNA translation and can be prevented by either reconstitution of OLA1 expression or treatment with an eIF2␣ dephosphorylation inhibitor, suggesting that OLA1 regulates p21 through a translational mechanism involving eIF2. With immunohistochemistry, overexpression of p21 protein was detected in Ola1-null embryos with reduced cell proliferation. Moreover, we have generated p21 ؊/؊ Ola1 ؊/؊ mice and found that knockout of p21 can partially rescue the growth retardation defect of Ola1 ؊/؊ embryos but fails to rescue them from developmental delay and the lethality. These data demonstrate, for the first time, that OLA1 is required for normal progression of mammalian development. OLA1 plays an important role in promoting cell proliferation at least in part through suppression of p21 and organogenesis via factors yet to be discovered. O LA1 belongs to the translation-factor-related (TRAFAC) class, Obg family, and YchF subfamily of P-loop GTPases (1-3). The TRAFAC GTPases include not only translation factors and ribosome-associated proteins but also proteins that are involved in signal transduction, intracellular transport, and stress responses (1, 2). The YchF/OLA1 proteins are highly conserved from bacteria to humans, and unlike other Obg family members, they possess both GTPase and ATPase activities (4-6). We recently revealed that human OLA1 is a eukaryotic initiation factor 2 (eIF2)-regulatory protein that suppresses protein synthesis and enhances the integrated stress response (ISR) by binding eIF2 and interfering with the formation of the eIF2-GTP-Met-tRNAi Met (ternary) complex (6).It is currently unclear whether YchF/OLA1 proteins are essential for life. Whereas most null mutations of the YchF homologue in yeasts are nonlethal (7), inactivation of TcYchF by RNA interference (RNAi) in trypanosomes (Trypanosoma cruzi) inhibited the protozoan's growth (4). We (6) and others (8) reported that OLA1 knockdown (KD) in human cells under normal culture conditions had, depending on the origin of the cell lines used, either a negative effect or no effect on cell proliferation. However, under multiple cellular stresses, including oxidative stress, OLA1 KD promoted cell survival (9) by "gating" ISR and the expression of downstream proapoptotic factors, such as CHOP (6). These paradoxical findings suggest that OLA1 plays multiple roles in the regulation of cell proliferation and cell survival. This provides ...

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Section: Discussionmentioning

confidence: 87%

OLA1, a Translational Regulator of p21, Maintains Optimal Cell Proliferation Necessary for Developmental Progression

Ding

Liu

Rubio

et al. 2016

Molecular and Cellular Biology

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“…In this study, OLA1 was reported to control protein synthesis and cell fate decisions in stressed cells as well as impacts the growth and progression of the tumour . Another study demonstrates the role of OLA1 in translation regulation thus identifying OLA1 as one of the three candidate genes important for cytoplasmic protein biosynthesis in yeast …”

Section: Introductionmentioning

confidence: 77%

“…However, our findings establish the downstream signalling mechanisms that are involved in OLA1‐mediated decrease in hypertrophic response. OLA1 possesses GTPase and ATPase activities and has been shown to play a role in protein translation and synthesis . Previous reports have shown that OLA1 mediates GSK3β phosphorylation (Ser9) in lung cancer .…”

Section: Discussionmentioning

confidence: 99%

OBG‐like ATPase 1 inhibition attenuates angiotensin II‐induced hypertrophic response in human ventricular myocytes via GSK‐3beta/beta‐catenin signalling

Narasimhan

Henderson

Luong

et al. 2019

Clin Exp Pharma Physio

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Obg‐like ATPase 1 (OLA1) that possesses both GTP and ATP hydrolyzing activities has been shown to be involved in translational regulation of cancer cell growth and survival. Also, GSK3β signalling has been implicated in cardiac development and disease. However, the role of OLA1 in pathological cardiac hypertrophy is unknown. We sought to understand the mechanism by which OLA1 regulates GSK3β‐β‐Catenin signalling and its functional significance in angiotensin‐II (ANG II)‐induced cardiac hypertrophic response. OLA1 function and its endogenous interaction with GSK3β/β‐catenin signalling in cultured human ventricular cardiomyocytes (AC16 cells) and mouse hearts (in vivo) was evaluated with/without ANG II‐stimulated hypertrophic response. ANG II administration in mice increases myocardial OLA1 protein expression with a corresponding increase in GSK3β phosphorylation and decrease in β‐Catenin phosphorylation. Cultured cardiomyocytes treated with ANG II show endogenous interaction between OLA1 and GSK3β, nuclear accumulation of β‐Catenin and significant increase in cell size and expression of hypertrophic marker genes such as atrial natriuretic factor (ANF; NPPA) and β‐myosin heavy chain (MYH7). Intriguingly, OLA1 inhibition attenuates the above hypertrophic response in cardiomyocytes. Taken together, our data suggest that OLA1 plays a detrimental role in hypertrophic response via GSK3β/β‐catenin signalling. Translation strategies to target OLA1 might potentially limit the underlying molecular derangements leading to left ventricular dysfunction in patients with maladaptive cardiac hypertrophy.

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“…2C). Ola1, a superaggregating cytosolic protein previously implicated in translation termination (Samanfar et al, 2014), also forms foci colocalized with Pab1. These four proteins are all thus bona fide heat shock granule components.…”

Section: Resultsmentioning

confidence: 99%

Reversible, Specific, Active Aggregates of Endogenous Proteins Assemble upon Heat Stress

Wallace

Kear-Scott

Pilipenko

et al. 2015

Cell

447

512

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Summary Heat causes protein misfolding and aggregation, and in eukaryotic cells triggers aggregation of proteins and RNA into stress granules. We have carried out extensive proteomic studies to quantify heat-triggered aggregation and subsequent disaggregation in budding yeast, identifying more than 170 endogenous proteins aggregating within minutes of heat shock in multiple subcellular compartments. We demonstrate that these aggregated proteins are not misfolded and destined for degradation. Stable-isotope labeling reveals that even severely aggregated endogenous proteins are disaggregated without degradation during recovery from shock, contrasting with the rapid degradation observed for exogenous thermolabile proteins. Although aggregation likely inactivates many cellular proteins, in the case of a heterotrimeric aminoacyl-tRNA synthetase complex, the aggregated proteins remain active with unaltered fidelity. We propose that most heat-induced aggregation of mature proteins reflects the operation of an adaptive, autoregulatory process of functionally significant aggregate assembly and disassembly that aids cellular adaptation to thermal stress.

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A global investigation of gene deletion strains that affect premature stop codon bypass in yeast, Saccharomyces cerevisiae

Cited by 37 publications

References 37 publications

OLA1, a Translational Regulator of p21, Maintains Optimal Cell Proliferation Necessary for Developmental Progression

OLA1, a Translational Regulator of p21, Maintains Optimal Cell Proliferation Necessary for Developmental Progression

OBG‐like ATPase 1 inhibition attenuates angiotensin II‐induced hypertrophic response in human ventricular myocytes via GSK‐3beta/beta‐catenin signalling

Reversible, Specific, Active Aggregates of Endogenous Proteins Assemble upon Heat Stress

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