Liu Group – University of Copenhagen

Liu Group

Molecular Aging Program
Center for Chromosome Stability
Center for Healthy Aging

Research activities

Current projects 1) Analysis of chromosomal abnormality at tri-nucleotide repeat (TNR) regions in cell lines derived from Fragile X syndrome

Repetitive sequences constitute 30% of the genome and are the common source of diversity. The tri-nucleotide repeat (TNR) is one type of repeat and can be problematic when it exceeds a crucial threshold length. For example, if the TNR lies within a crucial gene, it can cause severe disease. The mechanisms underlying the diseases associated with TNRs are not fully understood, and DNA replication and repair pathways are speculated to play an important role in their development. In this project, we use Fragile X Syndrome (FXS) cells as a model to study how the TNR regions are replicated. FXS is caused by a CGG repeat in the FRAXA region on chromosome X. The fully mutated FRAXA region (with 200 – 4000 repeat units) is prone to break when the cells are exposed to folic acid deficient growth medium, which is a phenomenon akin to that of common fragile sites (CFSs). We aim to decipher the mechanism underlying the ‘fragility’ of this type of TNR region using methods that have been applied to the studies of CFSs.

2) Post-Translational Modification of Proteins by Sumoylation in Response to DNA Replication stress

In response to replication-associated DNA damage, human cells activate a highly conserved signalling network to prevent irreversible breakdown of DNA replication forks. One component of this DNA damage response is post-translational modification of various proteins via one or more of the following mechanisms: phosphorylation, acetylation, mono- or polyubiquitylation and sumoylation. While a lot is known about how phosphorylation affects protein function, little information is available on the sumoylation of proteins following cellular stress. We have used an unbiased approach on a proteome-wide scale to identify proteins that are sumoylated constitutively and in response to DNA replication stress using mass spectrometry. The function of this modification in the target proteins are analyzed using molecular, genetic, and cell biological methods.

3) Identification of genes that would predispose sensitivity to radiotherapy in cancer patients

Radiotherapy is an effective treatment for the majority of cancer patients. However, a small portion of cancer patients (5-10%) would suffer significant toxicity from this treatment. The symptoms can vary from skin reddening to life-threatening reaction including pneumonitis, diarrhea, tissue or organ damage, and brain edema. To date, the cause for this ‘radiation-sensitivity’ is still unknown. We hypothesized that some of the reaction is caused by the DNA repair deficiency in these patients. In a normal environment, this deficiency would not be life-threatening for the patients. However, when the patients are exposed to radiotherapy that can cause damage specifically to DNA, the patients with those potential DNA repair deficiency would suffer more severely than those patients who have fully functional DNA repair systems. DNA samples of four cell lines derived from the lymphocytes of cancer patients who were sensitive to radiotherapy have been sequenced. Functional analysis of the candidate genes, including their post-translational modifications, will be carried out. The outcome of this project will be helpful for oncologist to design suitable treatment for cancer patients.