The DNA Repair Genomics Lab
Multiple processes in the nucleus can influence and be influenced by damage levels. These include RNA transcription, chromatin composition and architecture, DNA methylation and DNA replication. In our lab, we combine wet-lab experiments with computational analysis to study the interaction between these processes in human cells.
We focus on bulky, helix-distorting, DNA base-damages. These include carcinogenic damages induced by ultraviolet (UV) radiation in sunlight and cigarette smoke, as well as damages induced by platinum-based chemotherapy designed to kill cancer cells. In human cells, these damages are repaired by nucleotide excision repair (NER).
Our ability to map DNA damages and DNA repair at high resolution across the genome gives us unprecedented insight into the determinants of genome stability and cancer mutagenesis. Current projects in the lab include:
The relationship between DNA damage and transcription
Bulky DNA damages block transcription. At the same time, the blocked RNA polymerase itself recruits repair factors for transcription-coupled repair, and cell function requires certain transcripts to still be expressed. Using our damage and RNA mapping methods, we are studying in the intricacies of this relationship to understand what transcripts are necessary for the bulky DNA damage response and how their expression is maintained.
How do Transcription factors and DNA damage affect each other?
An under-studied question is how DNA damages affect transcription-regulation mediated by transcription factors. Transcription factors bind specific DNA sequences. Certain transcription factor binding sites (e.g. ETS1) are hotspots for damage formation. Furthermore, transcription factor binding appears to hinder repair. Together, both damage formation and lower repair could explain higher mutation rates at transcription factor binding sites. However, if and how damages affect transcription factor binding is unclear.
How do DNA damages lead to mutations?
The DNA damages we study block replication. However, specialized bypass polymerases can replicate them while inserting the wrong nucleotides, causing mutations. With the decline in sequencing costs, we are now able to study DNA damage formation, DNA repair and whole-genome scale mutagenesis in human cells lines to establish the determinants of specific mutational signatures.
What can we learn from cancer genomics on the processes of DNA damage and repair?
Recent cancer sequencing efforts uncovered specific mutational signatures that are associated with exposure to DNA damaging agents or defects in DNA repair. From analyzing cancer genomes, we can learn about the carcinogenic process specific cancers underwent. Our goal is to use this data to identify cancer risk and prognostic markers.
How does DNA repair contribute to cancer resistance to chemotherapy?
How do resistant and sensitive ovarian cancer cells respond and repair cisplatin-induced DNA damage? Can we pinpoint factors that contribute to cisplatin resistance using our DNA damage and repair maps and RNA-seq after cisplatin treatment?