Nucleotide Excision Repair Related Genes Discovery Through Integrative Genomics Approaches

Helix-distorting DNA damages block transcription and replication and compromise genome integrity and function. These include dimers induced by ultraviolet radiation (UV), and adducts induced by smoking or the chemotherapycisplatin. In human cells, these damages are repaired by Nucleotide Excision Repair (NER).

We systematically assayed transcription in response to NER related lesions in multiple cell types and damaging agents. The results indicated a general reduction in gene expression,associated with basic gene properties like gene length and sequence G-C composition.

By integrating previous genome-wide maps of damage and repair, we find that the downregulation of longer genes is due both to higher susceptibility to damage, and to lower repair.We previously showed exons are more efficiently repaired than introns, and find that the favorable repair of upregulated genes can be explained by enrichment of exonic sequences.While transcription is generally reduced, we identified a set of genes that are consistently upregulated. This upregulation suggests a functional significance for these genes in the cellular response to bulky lesions. These genes are currently being studied in the lab and could be interesting candidates for future cancer susceptibility and therapy strategies.