Post-transcriptional control of DNA damage responses

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Our deoxyribonucleic acid (DNA) is constantly exposed to damaging agents that challenge the integrity of our genetic information. Human DNA contains almost 30 000 genes that provide the full set of instructions to produce all of the proteins required for life. Our DNA is found in the nucleus while proteins are made in ribosomes that are physically separated in the cytoplasm of the cell. Messenger Ribonucleic acids (mRNAs) are used to transfer the genetic information from our genes (DNA) to the ribosomes in the cytoplasm for translation (protein synthesis). The life of the mRNA is complex. As it is produced, it undergoes extensive processing to remove intervening sequences (introns) that are not required to encode proteins. In addition, the ends of the mRNAs are modified to protect them and they become coated with proteins that help them on their journey to ribosomes. The transcription of genes to make mRNAs is required but is certainly not sufficient to regulate protein production. Recent evidence, including some work from my laboratory, indicates that many mRNAs are triaged, degraded and fail to exit the nucleus as a means of quality control. We find that DNA damage responses affect these molecular genetic decisions. We propose to study how the RNA processing steps (from DNA to protein) are changed in cells that are exposed to DNA damage using state-of-the-art functional genomic approaches. Our work promises to provide important insight into the ways we deal with the constant onslaught of DNA damage coming from our internal and external environments.