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Alternative transcript initiation and splicing as a response to DNA damage.

Sprung CN, Li J, Hovan D, McKay MJ, Forrester HB - PLoS ONE (2011)

Bottom Line: 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.This study provides novel insights into alternative transcripts as a mechanism for response to DNA damage and cell stress responses in general.

View Article: PubMed Central - PubMed

Affiliation: Centre for Innate Immunity and Infectious Disease, Monash Institute for Medical Research, Monash University, Clayton, Victoria, Australia. carl.sprung@monash.edu

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.

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Gene network in response to IR.Genes such as CDKN1A and MDM2 are central in this network. Solid lines represent direct protein interactions and dashed lines represent indirect interactions. Different shapes correspond to different gene ontological groupings (Ingenuity Pathway Analysis). Shaded genes are genes that are in the top 100 up-regulated (red) and top 100 down-regulated (green) genes shown to be modulated at 4 hours following 10 Gy IR in LCLs.
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pone-0025758-g012: Gene network in response to IR.Genes such as CDKN1A and MDM2 are central in this network. Solid lines represent direct protein interactions and dashed lines represent indirect interactions. Different shapes correspond to different gene ontological groupings (Ingenuity Pathway Analysis). Shaded genes are genes that are in the top 100 up-regulated (red) and top 100 down-regulated (green) genes shown to be modulated at 4 hours following 10 Gy IR in LCLs.

Mentions: Gene functional ontologies for the IR regulated genes were determined and cell cycle, cellular assembly and organization, DNA replication, recombination and repair, cell death and cellular movement were the top 5 functional categories in LCLs as determined by Ingenuity Pathway Analysis (Figure S1A). p53 signalling, molecular mechanisms of cancer, and cell cycle: G2/M DNA damage checkpoint regulation were the top three pathway categories (Figure S1B). Gene functional ontologies for the IR regulated genes were also determined in the fibroblast cells and the top categories were similar to the LCL cells, with cell death as the most prominent, and cell morphology also ranked highly (Figure S1C). p53 signalling also was the top pathway for the fibroblast IR response gene set (Figure S1D). Networks of the top 100 up- and down-regulated genes were determined with the IPA package. A large network, revolving around p53 (although p53 itself was not modulated significantly at the transcript level), CDKN1A, cyclins, TNF and PLK genes, was obtained (Figures 12 and S2).


Alternative transcript initiation and splicing as a response to DNA damage.

Sprung CN, Li J, Hovan D, McKay MJ, Forrester HB - PLoS ONE (2011)

Gene network in response to IR.Genes such as CDKN1A and MDM2 are central in this network. Solid lines represent direct protein interactions and dashed lines represent indirect interactions. Different shapes correspond to different gene ontological groupings (Ingenuity Pathway Analysis). Shaded genes are genes that are in the top 100 up-regulated (red) and top 100 down-regulated (green) genes shown to be modulated at 4 hours following 10 Gy IR in LCLs.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198437&req=5

pone-0025758-g012: Gene network in response to IR.Genes such as CDKN1A and MDM2 are central in this network. Solid lines represent direct protein interactions and dashed lines represent indirect interactions. Different shapes correspond to different gene ontological groupings (Ingenuity Pathway Analysis). Shaded genes are genes that are in the top 100 up-regulated (red) and top 100 down-regulated (green) genes shown to be modulated at 4 hours following 10 Gy IR in LCLs.
Mentions: Gene functional ontologies for the IR regulated genes were determined and cell cycle, cellular assembly and organization, DNA replication, recombination and repair, cell death and cellular movement were the top 5 functional categories in LCLs as determined by Ingenuity Pathway Analysis (Figure S1A). p53 signalling, molecular mechanisms of cancer, and cell cycle: G2/M DNA damage checkpoint regulation were the top three pathway categories (Figure S1B). Gene functional ontologies for the IR regulated genes were also determined in the fibroblast cells and the top categories were similar to the LCL cells, with cell death as the most prominent, and cell morphology also ranked highly (Figure S1C). p53 signalling also was the top pathway for the fibroblast IR response gene set (Figure S1D). Networks of the top 100 up- and down-regulated genes were determined with the IPA package. A large network, revolving around p53 (although p53 itself was not modulated significantly at the transcript level), CDKN1A, cyclins, TNF and PLK genes, was obtained (Figures 12 and S2).

Bottom Line: 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.This study provides novel insights into alternative transcripts as a mechanism for response to DNA damage and cell stress responses in general.

View Article: PubMed Central - PubMed

Affiliation: Centre for Innate Immunity and Infectious Disease, Monash Institute for Medical Research, Monash University, Clayton, Victoria, Australia. carl.sprung@monash.edu

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.

Show MeSH
Related in: MedlinePlus