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The g-tubulin meshwork assists to the transport of cytosolic PCNA to chromatin in mammalian cells

ABSTRACT: Changes in the location of g-tubulin ensure cell survival and preserve genome integrity. We investigated whether the nuclear accumulation of g-tubulin facilitates the transport of proliferating cell nuclear antigen (PCNA) between the cytosolic and the nuclear compartment in mammalian cells. We found that the g-tubulin meshwork assists to the recruitment of PCNA to chromatin. Also, decreased levels of g-tubulin reduce the nuclear pool of PCNA. In addition, the g-tubulin C terminus encodes a PCNA-interacting peptide (PIP) motif, and a g-tubulin–PIP-mutant affects the nuclear accumulation of PCNA. In a cell-free system, PCNA and g-tubulin formed a complex. In tumors, there is a significant positive correlation between TUBG1 and PCNA expression. Thus, we report a novel mechanism that constitutes the basis for tumor growth by which the g-tubulin meshwork maintains indefinite proliferation by acting as an opportune scaffold for the transport of PCNA from the cytosol to the chromatin.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148798 | GEO | 2021/04/17

REPOSITORIES: GEO

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The g-tubulin meshwork assists to the transport of cytosolic PCNA to chromatin in mammalian cells

Project description:Changes in the location of g-tubulin ensure cell survival and preserve genome integrity. We investigated whether the nuclear accumulation of g-tubulin facilitates the transport of proliferating cell nuclear antigen (PCNA) between the cytosolic and the nuclear compartment in mammalian cells. We found that the g-tubulin meshwork assists to the recruitment of PCNA to chromatin. Also, decreased levels of g-tubulin affected the nuclear pool of PCNA. In addition, the g-tubulin C terminus encodes a PCNA-interacting peptide (PIP) motif, and a g-tubulin–PIP-mutant affects the nuclear accumulation of PCNA. In a cell-free system, PCNA and g-tubulin formed a complex. In tumors, there is a significant positive correlation between TUBG1 and PCNA expression. Thus, we report a novel mechanism that constitutes the basis for tumor growth by which the g-tubulin meshwork maintains indefinite proliferation by acting as an opportune scaffold for the transport of PCNA from the cytosol to the chromatin.

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The g-tubulin meshwork assists to the transport of cytosolic PCNA to chromatin in mammalian cells

Project description:The g-tubulin meshwork assists to the transport of cytosolic PCNA to chromatin in mammalian cells

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The g-tubulin meshwork assists to the transport of cytosolic PCNA to chromatin in mammalian cells

Project description:The g-tubulin meshwork assists to the transport of cytosolic PCNA to chromatin in mammalian cells

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Investigation of the gamma-tubulin binding site in the nuclear and mitochondrial DNA of cells in S-phase

Project description:In a cell, g-tubulin establishes a cellular network of threads named g-string meshwork. However, the functions of this meshwork remain to be determined. We investigated the traits of the meshwork and show that g-strings have the ability to connect the cytoplasm and the mitochondrial DNA together. We also show that g-tubulin has a role in the maintenance of the mitochondrial meshwork and homeostasis as reduced levels of g-tubulin or impairment of its GTPase domain disrupts the mitochondria network and alters both their respiratory capacity and the expression of mitochondria-related genes. By contrast, reduced mitochondria number or increased protein levels of g-tubulin DNA-binding domain favour the association of g-tubulin with mitochondria. Our results demonstrate that g-tubulin is an important mitochondrial structural component that maintains the mitochondria meshwork, providing mitochondria with a cellular infrastructure. We propose that g-tubulin provides a cytoskeletal element that maintains mitochondria homeostasis and gives form to the mitochondria meshwork. Keywords: Genome binding/occupancy profiling by high throughput sequencing

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AOH1996, a small molecule ligand of PCNA, modulates PCNA interaction with RPB1

Project description:Targeting transcription replication conflicts, a major source of endogenous DNA double stranded breaks and genomic instability, could have important therapeutic implications. When transcription and DNA replication machineries encounter each other on chromosomes, one way to resolve the conflict is temporarily dislodging RNA polymerase II from the conflict sites to enable the replication fork to proceed. Proliferating cell nuclear antigen (PCNA), an essential component of replisomes, plays a critical role in this process. We discovered a small molecule ligand (AOH1996) of PCNA, which targets a binding pocket adjacent to the outer surface region of PCNA known to interact with PIP box and APIM motif proteins. Orally administrable, AOH1996 suppresses tumor growth but causes no discernable side effects. In addition, we found that AOH1996 treatment can stabilize interaction between PCNA and RPB1, the largest subunit of RNA polymerase II. To determine whether the effect of AOH1996 is mediated through affecting PCNA interaction with RPB1, we mutated Y418 within the APIM motif of RPB1 to an alanine in the SK-N-AS cell line by CRISPR and compared changes in protein expression profiles caused by AOH1996 in the parent and mutant SK-N-AS cells.

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The γ-tubulin meshwork assists in the recruitment of PCNA to chromatin in mammalian cells.

Project description:Changes in the location of γ-tubulin ensure cell survival and preserve genome integrity. We investigated whether the nuclear accumulation of γ-tubulin facilitates the transport of proliferating cell nuclear antigen (PCNA) between the cytosolic and the nuclear compartment in mammalian cells. We found that the γ-tubulin meshwork assists in the recruitment of PCNA to chromatin. Also, decreased levels of γ-tubulin reduce the nuclear pool of PCNA. In addition, the γ-tubulin C terminus encodes a PCNA-interacting peptide (PIP) motif, and a γ-tubulin-PIP-mutant affects the nuclear accumulation of PCNA. In a cell-free system, PCNA and γ-tubulin formed a complex. In tumors, there is a significant positive correlation between TUBG1 and PCNA expression. Thus, we report a novel mechanism that constitutes the basis for tumor growth by which the γ-tubulin meshwork maintains indefinite proliferation by acting as an opportune scaffold for the transport of PCNA from the cytosol to the chromatin.

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Ubiquitinated PCNA drives USP1 synthetic lethality in cancer

Project description:CRISPR Cas9-based functional genomics screening is a powerful approach for identifying and characterizing novel oncology drug targets. Here, we elucidate the synthetic lethal mechanism of deubiquitinating enzyme USP1 in cancers with underlying DNA damage vulnerabilities, specifically BRCA1/2 mutant tumors and a subset of BRCA1/2 wild-type (WT) tumors. In sensitive cells, pharmacological inhibition of USP1 leads to decreased DNA synthesis concomitant with the induction of S-phase-specific DNA damage. Genome-wide CRISPR-Cas9 screens identified RAD18 and UBE2K, which promote PCNA mono- and polyubiquitination respectively, as downstream mediators of USP1 dependency. The accumulation of mono- and polyubiquitinated PCNA following USP1 inhibition was associated with a reduction in total PCNA protein levels. Ectopic expression of WT and ubiquitin-dead K164R PCNA reversed USP1 inhibitor sensitivity. Our results demonstrate, for the first time, that USP1 dependency hinges on the aberrant processing of mono- and polyubiquitinated PCNA. Moreover, this mechanism of USP1 dependency extends beyond BRCA1/2 mutant tumors to a novel subset of BRCA1/2 WT cancer enriched in ovarian and lung lineages. We further show PARP and USP1 inhibition are strongly synergistic in BRCA1/2 mutant cell lines and xenograft models. We postulate USP1 dependency unveils a previously uncharacterized vulnerability linked to post-translational modifications of PCNA. Taken together, USP1 inhibition may represent a unique therapeutic strategy for BRCA1/2 mutant tumors and a subset of BRCA1/2 WT tumors.

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The tubulin code during cardiac hypertrophy and failure [IV]

Project description:A proliferated and post-translationally modified microtubule network underlies cellular growth in cardiac hypertrophy and contributes to contractile dysfunction in heart failure. Yet how the heart achieves this modified network is poorly understood. Determining how the “tubulin code” – the permutations of tubulin isoforms and post-translational modifications - is rewritten upon cardiac stress may provide new targets to modulate cardiac remodeling. Further, while tubulin can autoregulate its own expression, it is unknown if autoregulation is operant in the heart or tuned in response to stress. Here we use heart failure patient samples and murine models of cardiac remodeling to interrogate transcriptional, autoregulatory, and post-translational mechanisms that contribute to microtubule network remodeling at different stages of heart disease. We find that autoregulation is operant across tubulin isoforms in the heart and leads to an apparent disconnect in tubulin mRNA and protein levels in heart failure. We also find that within 4 hours of a hypertrophic stimulus and prior to cardiac growth, microtubule detyrosination is rapidly induced to help stabilize the network. This occurs concomitant with rapid transcriptional and autoregulatory activation of specific tubulin isoforms and microtubule motors. Upon continued hypertrophic stimulation, there is an increase in post-translationally modified microtubule tracks and anterograde motors to support cardiac growth, while total tubulin content increases through progressive transcriptional and autoregulatory induction of tubulin isoforms. Our work provides a new model for how the tubulin code is rapidly rewritten to establish a proliferated, stable microtubule network that drives cardiac remodeling, and provides the first evidence of tunable tubulin autoregulation during pathological progression.

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