Targeted Deletion of the Gene Encoding the La Autoantigen (Sjögren's Syndrome Antigen B) in B Cells or the Frontal Brain Causes Extensive Tissue Loss

Gaidamakov, Sergei; Maximova, Olga A.; Chon, Hyongi; Blewett, Nathan H.; Wang, Hongsheng; Crawford, Amanda; Day, Amanda; Tulchin, Natalie; Crouch, Robert J.; Morse, Herbert C.; Blitzer, Robert D.; Maraia, Richard J

doi:10.1128/mcb.01010-13

Cited by 24 publications

(35 citation statements)

References 72 publications

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“…La was readily detected in nuclei throughout WT cortex but was very much reduced in La cKO cortex (Fig. 5, ␣-La), in good agreement with prior results (46). A relatively low level of GFAP was observed in WT cortex but was more extensive in La cKO cortex (Fig.…”

supporting

confidence: 81%

“…Defective processing of pre-tRNA Tyr has been documented. Specifically, La cKO cortex exhibited substantial decrease of a 3= trailer-containing spliced pre-tRNA Tyr but not the nascent 3= trailer-containing pre-tRNA Tyr (46), which is surprising, because both are expected to be similarly protected by La and labile in its absence (12,15,47). In any case, the data are consistent with reports that indicate neuronal sensitivity to faulty tRNA biogenesis (48)(49)(50); reviewed in reference 51).…”

supporting

confidence: 81%

“…Importantly, Fig. 6A revealed that the onset of GFAP reactivity roughly coincided with the onset of loss of La cKO cortical mass previously reported (46) and with the neuronal degeneration seen in Fig. 4.…”

mentioning

confidence: 71%

“…La cKO brains are normal until ϳ6 weeks and then fail to gain mass at the normal rate and by 12 to 13 weeks begin to lose cortical mass relative to controls (46). Defective processing of pre-tRNA Tyr has been documented.…”

mentioning

confidence: 99%

“…Conditional deletion of La by CaMKII␣-Cre revealed that brain mass begins to decline at 12 to 13 weeks of age and continues for several weeks thereafter, with the first evidence of altered brain morphology at 16 weeks (46). We performed transcriptome sequencing (RNA-Seq) on 16-week cortices from WT and La cKO mice.…”

mentioning

confidence: 99%

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La Deletion from Mouse Brain Alters Pre-tRNA Metabolism and Accumulation of Pre-5.8S rRNA, with Neuron Death and Reactive Astrocytosis

Blewett

Iben

Gaidamakov

et al. 2017

Molecular and Cellular Biology

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Human La antigen (Sjögren's syndrome antigen B [SSB]) is an abundant multifunctional RNA-binding protein. In the nucleoplasm, La binds to and protects from 3= exonucleases, the ends of precursor tRNAs, and other transcripts synthesized by RNA polymerase III and facilitates their maturation, while a nucleolar isoform has been implicated in rRNA biogenesis by multiple independent lines of evidence. We showed previously that conditional La knockout (La cKO) from mouse cortex neurons results in defective tRNA processing, although the pathway(s) involved in neuronal loss thereafter was unknown. Here, we demonstrate that La is stably associated with a spliced pre-tRNA intermediate. Microscopic evidence of aberrant nuclear accumulation of 5.8S rRNA in La cKO is supported by a 10-fold increase in a pre-5.8S rRNA intermediate. To identify pathways involved in subsequent neurodegeneration and loss of brain mass in the cKO cortex, we employed mRNA sequencing (mRNASeq), immunohistochemistry, and other approaches. This revealed robust enrichment of immune and astrocyte reactivity in La cKO cortex. Immunohistochemistry, including temporal analyses, demonstrated neurodegeneration, followed by astrocyte invasion associated with immune response and decreasing cKO cortex size over time. Thus, deletion of La from postmitotic neurons results in defective pre-tRNA and prerRNA processing and progressive neurodegeneration with loss of cortical brain mass.KEYWORDS La protein, pre-rRNA, tRNA maturation, tRNA splicing L a was described as a component of ribonucleoprotein particles (RNPs) targeted by autoantibodies in patients suffering from systemic lupus erythematosus and Sjögren's syndrome (1) and was later found in all free-living eukaryotes (2). La is an abundant RNA-binding protein that recognizes UUU-3=-OH, which results from transcription termination by RNA polymerase III (RNAP III) (3-5). This conserved activity functions to protect nascent RNAs from 3= exonucleases, including the nuclear exosome Rrp6, and facilitates the ordered processing and maturation of these transcripts, the more abundant of which are the precursor tRNAs (6-12, 15; reviewed in references 13 and 14).In addition to 3=-end protection, La also exhibits RNA chaperone activity, which serves to prevent misfolding of the pre-tRNA sequences with a propensity to form alternate structures (8,14,16,17). The RNA chaperone activity works with the 3= protection activity to assist structurally challenged pre-tRNAs that would otherwise succumb to nuclear surveillance via exosome Rrp6-mediated decay (9,10,15,18,19).La is nonessential in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe (14, 137) but is essential during Drosophila melanogaster and Mus musculus development (20, 21), suggesting that its role in RNAP III transcript maturation is

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supporting

confidence: 81%

supporting

confidence: 81%

mentioning

confidence: 71%

mentioning

confidence: 99%

mentioning

confidence: 99%

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La Deletion from Mouse Brain Alters Pre-tRNA Metabolism and Accumulation of Pre-5.8S rRNA, with Neuron Death and Reactive Astrocytosis

Blewett

Iben

Gaidamakov

et al. 2017

Molecular and Cellular Biology

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The RNA‐binding protein La/SSB associates with radiation‐induced DNA double‐strand breaks in lung cancer cell lines

Staudacher

Liapis

et al. 2021

Cancer Reports

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Background Platinum‐based chemotherapy and radiotherapy are standard treatments for non‐small cell lung cancer, which is the commonest, most lethal cancer worldwide. As a marker of treatment‐induced cancer cell death, we have developed a radiodiagnostic imaging antibody, which binds to La/SSB. La/SSB is an essential, ubiquitous ribonuclear protein, which is over expressed in cancer and plays a role in resistance to cancer therapies. Aim In this study, we examined radiation‐induced DNA double strand breaks (DSB) in lung cancer cell lines and examined whether La/SSB associated with these DSB. Method Three lung cancer lines (A549, H460 and LL2) were irradiated with different X‐ray doses or X‐radiated with a 5 Gy dose and examined at different time‐points post‐irradiation for DNA DSB in the form of γ‐H2AX and Rad51 foci. Using fluorescence microscopy, we examined whether La/SSB and γ‐H2AX co‐localise and performed proximity ligation assay (PLA) and co‐immunoprecipitation to confirm the interaction of these proteins. Results We found that the radio‐resistant A549 cell line compared to the radio‐sensitive H460 cell line showed faster resolution of radiation‐induced γ‐H2AX foci over time. Conversely, we found more co‐localised γ‐H2AX and La/SSB foci by PLA in irradiated A549 cells. Conclusion The co‐localisation of La/SSB with radiation‐induced DNA breaks suggests a role of La/SSB in DNA repair, however further experimentation is required to validate this.

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Positron Emission Tomographic Imaging of Tumor Cell Death Using Zirconium-89-Labeled APOMAB® Following Cisplatin Chemotherapy in Lung and Ovarian Cancer Xenograft Models

et al. 2021

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Purpose Early detection of tumor treatment responses represents an unmet clinical need with no approved noninvasive methods. DAB4, or its chimeric derivative, chDAB4 (APOMAB®) is an antibody that targets the Lupus associated antigen (La/SSB). La/SSB is over-expressed in malignancy and selectively targeted by chDAB4 in cancer cells dying from DNA-damaging treatment. Therefore, chDAB4 is a unique diagnostic tool that detects dead cancer cells and thus could distinguish between treatment responsive and nonresponsive patients. Procedures In clinically relevant tumor models, mice bearing subcutaneous xenografts of human ovarian or lung cancer cell lines or intraperitoneal ovarian cancer xenografts were untreated or given chemotherapy followed 24h later by chDAB4 radiolabeled with [89Zr]ZrIV. Tumor responses were monitored using bioluminescence imaging and caliper measurements. [89Zr]Zr-chDAB4 uptake in tumor and normal tissues was measured using an Albira SI Positron-Emission Tomography (PET) imager and its biodistribution was measured using a Hidex gamma-counter. Results Tumor uptake of [89Zr]Zr-chDAB4 was detected in untreated mice, and uptake significantly increased in both human lung and ovarian tumors after chemotherapy, but not in normal tissues. Conclusion Given that tumors, rather than normal tissues, were targeted after chemotherapy, these results support the clinical development of chDAB4 as a radiodiagnostic imaging agent and as a potential predictive marker of treatment response.

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Targeted Deletion of the Gene Encoding the La Autoantigen (Sjögren's Syndrome Antigen B) in B Cells or the Frontal Brain Causes Extensive Tissue Loss

Cited by 24 publications

References 72 publications

La Deletion from Mouse Brain Alters Pre-tRNA Metabolism and Accumulation of Pre-5.8S rRNA, with Neuron Death and Reactive Astrocytosis

La Deletion from Mouse Brain Alters Pre-tRNA Metabolism and Accumulation of Pre-5.8S rRNA, with Neuron Death and Reactive Astrocytosis

The RNA‐binding protein La/SSB associates with radiation‐induced DNA double‐strand breaks in lung cancer cell lines

Positron Emission Tomographic Imaging of Tumor Cell Death Using Zirconium-89-Labeled APOMAB® Following Cisplatin Chemotherapy in Lung and Ovarian Cancer Xenograft Models

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