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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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Related in: MedlinePlus

Lymphoblastoid and fibroblast cells show different transcription responses to IR.Gene expression (as determined from exon microarrays) across the BAX (A, B) and THSD1P (C, D) genes are graphed for each PSR 4 hours after 10 Gy IR (blue line) or sham treated (red line) in LCLs (A, C) or fibroblasts (B, D). n = 6 and SEM is graphed for each PSR.
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pone-0025758-g006: Lymphoblastoid and fibroblast cells show different transcription responses to IR.Gene expression (as determined from exon microarrays) across the BAX (A, B) and THSD1P (C, D) genes are graphed for each PSR 4 hours after 10 Gy IR (blue line) or sham treated (red line) in LCLs (A, C) or fibroblasts (B, D). n = 6 and SEM is graphed for each PSR.

Mentions: There is a high degree of overlap for radiation modulated whole gene expression between LCLs and fibroblasts. ED2A (Figures 1A and 2A), CDKN1A (Figures 1C and 2C), MDM2 (Figures 4C and 5B) and FBXW7 (Figures 4D and 5C) are a few examples. However, there are genes that show cell type specific modulation in response to IR 4 hours after exposure. For example, BAX, BCL2, RRM2B and ATF3 are induced in LCLs but not in fibroblasts, and THSP1 and PAG1 are induced in fibroblasts but not LCLs. Two representative genes (BAX and THSD1P) are shown in Figure 6. Also, there is generally a more robust expression response at four hours post-IR across the whole gene in LCLs compared to fibroblasts. For example, the fold change for the top 20 up-regulated genes 4 hours after 10 Gy IR range from 1.72 (for TNFRSF10B) to 3.79 (for PLK2) for LCLs (Table 1) and only from 1.36 (ZNF79) to 2.63 (CDKN1A) in fibroblast cells (Table 2). Similarly, the fold change for the top down-regulated genes 4 hours after 10 Gy IR ranged from −1.38 (INCENP) to −4.63 (KIF20A) for LCLs (Table 3) and only −1.19 (SETD8) to −2.63 (AURKA) for fibroblasts (Table 4). Also the difference in the robustness of the results between LCL and fibroblasts is apparent when comparing the values of fold change between some genes common to both lists. For example, CDKN1A which has a fold increase of 2.94 in LCLs compared to 2.63 in fibroblasts, and EDA2R has a fold change of 2.67 in LCLs compared to 1.57 in fibroblast cells (Tables 1 and 2).


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

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

Lymphoblastoid and fibroblast cells show different transcription responses to IR.Gene expression (as determined from exon microarrays) across the BAX (A, B) and THSD1P (C, D) genes are graphed for each PSR 4 hours after 10 Gy IR (blue line) or sham treated (red line) in LCLs (A, C) or fibroblasts (B, D). n = 6 and SEM is graphed for each PSR.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0025758-g006: Lymphoblastoid and fibroblast cells show different transcription responses to IR.Gene expression (as determined from exon microarrays) across the BAX (A, B) and THSD1P (C, D) genes are graphed for each PSR 4 hours after 10 Gy IR (blue line) or sham treated (red line) in LCLs (A, C) or fibroblasts (B, D). n = 6 and SEM is graphed for each PSR.
Mentions: There is a high degree of overlap for radiation modulated whole gene expression between LCLs and fibroblasts. ED2A (Figures 1A and 2A), CDKN1A (Figures 1C and 2C), MDM2 (Figures 4C and 5B) and FBXW7 (Figures 4D and 5C) are a few examples. However, there are genes that show cell type specific modulation in response to IR 4 hours after exposure. For example, BAX, BCL2, RRM2B and ATF3 are induced in LCLs but not in fibroblasts, and THSP1 and PAG1 are induced in fibroblasts but not LCLs. Two representative genes (BAX and THSD1P) are shown in Figure 6. Also, there is generally a more robust expression response at four hours post-IR across the whole gene in LCLs compared to fibroblasts. For example, the fold change for the top 20 up-regulated genes 4 hours after 10 Gy IR range from 1.72 (for TNFRSF10B) to 3.79 (for PLK2) for LCLs (Table 1) and only from 1.36 (ZNF79) to 2.63 (CDKN1A) in fibroblast cells (Table 2). Similarly, the fold change for the top down-regulated genes 4 hours after 10 Gy IR ranged from −1.38 (INCENP) to −4.63 (KIF20A) for LCLs (Table 3) and only −1.19 (SETD8) to −2.63 (AURKA) for fibroblasts (Table 4). Also the difference in the robustness of the results between LCL and fibroblasts is apparent when comparing the values of fold change between some genes common to both lists. For example, CDKN1A which has a fold increase of 2.94 in LCLs compared to 2.63 in fibroblasts, and EDA2R has a fold change of 2.67 in LCLs compared to 1.57 in fibroblast cells (Tables 1 and 2).

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