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Half-life and rate of synthesis of globin messenger ribonucleic acid. Determination of half-life of messenger ribonucleic acid and its relative synthetic rate in erythroid cells.

ABSTRACT: The specific radioactivity of mouse globin mRNA in blood reticulocytes was measured after injection of [(3)H]uridine into anaemic mice up to 60h before collection of reticulocytes. From these data, the decay of the acid-soluble nucleotide pool in the marrow and the relative marrow-cell composition it is possible to build models that allow the cell life-times and half-life of mRNA in the erythroid cells of the marrow to be calculated. Best fit of models to these data favour a model with either one or two cell divisions from the onset of mRNA synthesis. The single-cell-division model has cell times of 20, 13 and 7h respectively for the basophilic erythroblast, polychromatophilic erythroblast and reticulocyte. The two-cell-division model has cell times of 12, 12, 12 and 7h for the basophilic erythroblast 1 and 2, polychromatophilic erythroblast and reticulocyte respectively. Both models have an mRNA half-life of 17h and a constant rate of mRNA synthesis until enucleation at the reticulocyte stage, when synthesis stops. A declining rate of mRNA synthesis can be accommodated in a two-cell-division model, when synthesis halves at each cell division and cell times are essentially the same as above, but mRNA half-life is either 9h in the basophilic and polychromatophilic erythroblasts and 17h in the later cells, or 10h in the basophilic erythroblasts and polychromatophilic erythroblasts and 14.5h in later cells. In all cases it is clear that mRNA synthesis occurs over a time-period of only 30-36h and that mRNA cannot be pre-synthesized in precursor erythroid cells.

SUBMITTER: Hunt JA

PROVIDER: S-EPMC1166235 | biostudies-other | 1974 Mar

REPOSITORIES: biostudies-other

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Project description:Introduction: Case-control analyses have shown BARD1 variants to be associated with up to >2-fold increase in risk of breast cancer, and potentially greater risk of triple negative breast cancer. BARD1 is included in several gene sequencing panels currently marketed for the prediction of risk of cancer, however there are no gene-specific guidelines for the classification of BARD1 variants. We present the most comprehensive assessment of BARD1 messenger RNA splicing, and demonstrate the application of these data for the classification of truncating and splice site variants according to American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. Methods: Nanopore sequencing, short-read RNA-seq (whole transcriptome and targeted), and capillary electrophoresis analysis were performed by four laboratories to investigate alternative BARD1 splicing in blood, breast, and fimbriae/ovary related specimens from non-cancer affected tissues. Splicing data were also collated from published studies of nine different tissues. The impact of the findings for PVS1 annotation was assessed for truncating and splice site variants. Results: We identified 62 naturally occurring alternative spliced BARD1 splicing events, including 19 novel events found by next generation sequencing and/or reverse transcription PCR analysis performed for this study. Quantitative analysis showed that naturally occurring splicing events causing loss of clinically relevant domains or nonsense mediated decay can constitute up to 11.9% of overlapping natural junctions, suggesting that aberrant splicing can be tolerated up to this level. Nanopore sequencing of whole BARD1 transcripts characterized 16 alternative isoforms from healthy controls, revealing that the most complex transcripts combined only two alternative splicing events. Bioinformatic analysis of ClinVar submitted variants at or near BARD1 splice sites suggest that all consensus splice site variants in BARD1 should be considered likely pathogenic, with the possible exception of variants at the donor site of exon 5. Conclusions: No BARD1 candidate rescue transcripts were identified in this study, indicating that all premature translation-termination codons variants can be annotated as PVS1. Furthermore, our analysis suggests that all donor and acceptor (IVS+/-1,2) variants can be considered PVS1 or PVS1_strong, with the exception of variants targeting the exon 5 donor site, that we recommend considering as PVS1_moderate.

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Half-life and rate of synthesis of globin messenger ribonucleic acid. Determination of half-life of messenger ribonucleic acid and its relative synthetic rate in erythroid cells.

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