Alternative Transcript Initiation and Splicing as a Response to DNA Damage

Abstract

Humans are exposed to the DNA damaging agent, ionizing radiation (IR), from background radiation, medical treatments, occupational and accidental exposures. IR causes changes in transcription, but little is known about alternative transcription in response to IR on a genome-wide basis. These investigations examine the response to IR at the exon level in human cells, using exon arrays to comprehensively characterize radiation-induced transcriptional expression products. Previously uncharacterized alternative transcripts that preferentially occur following IR exposure have been discovered. A large number of genes showed alternative transcription initiation as a response to IR. Dose-response and time course kinetics have also been characterized. Interestingly, most genes showing alternative transcript induction maintained these isoforms over the dose range and times tested. Finally, clusters of co-ordinately up- and down-regulated radiation response genes were identified at specific chromosomal loci. These data provide the first genome-wide view of the transcriptional response to ionizing radiation at the exon level. This study provides novel insights into alternative transcripts as a mechanism for response to DNA damage and cell stress responses in general.

RNA-Seq analysis discloses early senescence and nucleolar dysfunction triggered by Tdp1α depletion in Medicago truncatula

“…Two key DNA damage sensors, the DSB sensor MRE11 and the DNA nick sensor PARP genes (De Vos et al, 2012), were regulated by alternative splicing, while RNA-Seq highlighted the modulation of chromatin remodelling genes required for disruption of the nucleosome-DNA interactions and stimulating DNA repair (van Attikum and Gasser, 2005). The expression of alternative gene isoforms was identified as a mechanism of DNA damage response in human cells and similarly the RNA-Seq results clearly indicate that this mechanism is used as a response to Tdp1α depletion in M. truncatula (Sprung et al, 2011). Moreover, Sanchez-Pons et al (2011) identified changes in the expression of genes related to RNA processing, which predominantly occurs in the nucleolus, in maize embryos exposed to camptothecin.…”

The biology and clinical impact of genetic lesions in myeloid malignancies

“…In addition to mediating precursor messenger RNA (mRNA) processing, spliceosomal proteins have been shown to influence histone modifications via physical interactions with Polycomb group proteins, 13 activate transcription through direct and indirect regulation of RNA polymerase elongation, 14,15 and coordinate aspects of cellular response to DNA damage. 16,17 The mutual exclusivity of splicing pathway mutations indicates that these alterations are either functionally redundant or that more significant disruption of canonical or noncanonical spliceosome activity is not tolerated by the cell.…”

Comparable dose estimates of blinded whole blood samples are obtained independently of culture conditions and analytical approaches. Second RENEB gene expression study

“…In ex vivo studies, several protocols have been used such as cultured peripheral blood mononuclear cells (PBMC) (Dressman et al 2007;Meadows et al 2008Meadows et al , 2010Sprung et al 2011;Boldt et al 2012;Knops et al 2012;Riecke et al 2012;Macaeva et al 2016), cultured whole blood diluted with media Brzoska andKruszewski 2015, Abend et al 2016) or undiluted whole blood (Manning et al 2013). However, none of these studies have addressed the role of blood culture methods during the incubation time at 37 C following radiation exposure.…”