Research

The DNA in each of our cells is damaged thousands of times every day, threatening genome stability and organismal health. A suite of dedicated enzymes detects and repairs damaged DNA; however, they can become dysregulated: In some individuals, DNA repair is inefficient and fails to repair DNA damage, leading to mutations that increase the risk of cancer and other diseases. In other cases, cancerous cells can hijack the DNA repair machinery to resist chemotherapy, leading to treatment failure.

The Laverty lab uses a combination of nucleic acid chemistry, biochemistry, and molecular biology to understand how human cells respond to DNA damage and how this relates to human health and disease. Our research can be divided into two main areas:

1. Molecular mechanisms of DNA double strand break repair and translesion synthesis

DNA is damaged in myriad ways, resulting in lesions with distinct biological outcomes. In dividing cells, DNA lesions that escape the repair machinery can block replication, eventually triggering cell death. Cells employ damage tolerance pathways such as translesion synthesis that allow them to restart replication and resist the toxic effects of unrepaired DNA damage. In the absence of these pathways, seemingly minor DNA lesions can be converted to highly toxic double strand breaks. We're interested in the interplay between gap-filling translesion synthesis and DNA double strand break repair, with a special interest in the repair of complex DNA double strand breaks.

2. Targeting mutagenic DNA repair and damage tolerance pathways to overcome treatment resistance in cancer

Frontline cancer treatments including radiotherapy, cisplatin, and temozolomide exert their antineoplastic effects by inflicting lethal DNA damage in cancer cells. Other therapies such as PARP inhibitors interfere with DNA replication, leading to single-stranded DNA gaps that are lethal to BRCA-deficient cancers. Despite the success of these therapies, many cancers are intrinsically resistant to therapy or develop resistance over the course of treatment. By employing newly developed functional assays in treatment resistant cancer models, we hope to understand how mutagenic DNA repair and damage tolerance pathways such as translesion synthesis contribute to treatment resistance.