Genomic predictors of interindividual differences in response to DNA damaging agents.
Human lymphoblastoid cells derived from different healthy individuals display considerable variation in their transcription profiles. Here we show that such variation in gene expression underlies interindividual susceptibility to DNA damaging agents. The results demonstrate the massive differences in sensitivity across a diverse cell line panel exposed to an alkylating agent. Computational models identified 48 genes with basal expression that predicts susceptibility with 94% accuracy. Modulating transcript levels for two member genes, MYH and C21ORF56, confirmed that their expression does indeed influence alkylation sensitivity. Many proteins encoded by these genes are interconnected in cellular networks related to human cancer and tumorigenesis.
Fry
Rebecca C
RC
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Svensson
J Peter
JP
Valiathan
Chandni
C
Wang
Emma
E
Hogan
Brad J
BJ
Bhattacharya
Sanchita
S
Bugni
James M
JM
Whittaker
Charles A
CA
Samson
Leona D
LD
D000477:Alkylating Agents / Q000633:toxicity; D002460:Cell Line; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D015894:Genome, Human; D006801:Humans; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D009153:Mutagens / Q000633:toxicity*; D016366:Open Reading Frames; D025521:Tumor Suppressor Proteins / Q000235:genetics
D000477:Alkylating Agents; D009153:Mutagens; D025521:Tumor Suppressor Proteins; D008769:Methylnitronitrosoguanidine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D045643:DNA Repair Enzymes