Kiranjit Dhillon

Joined Program: 2001
Previous Degree: B.S. Biology, Western Washington University
Monnat Lab
kkd (at) u.washington.edu

Research:
The focus of my thesis project is the analysis of in vivo functions of the Werner syndrome protein. Werner syndrome (WS) is one of three human RecQ helicase deficiency syndromes characterized by genetic instability and an elevated risk of cancer. WS also mimics aspects of accelerated or premature aging and includes an elevated risk of several important age-associated diseases. Cardiovascular disease and neoplasia are the predominant causes of death at an average age of 47. WS patients have frameshift, nonsense, and/or insertion/deletion mutations in the WRN gene and lack detectable WRN protein. Biochemical studies have identified 3’-5’ exonuclease and helicase activities of WRN. Additionally, WRN has been shown to physically or functionally interact with proteins involved in DNA repair, recombination, and replication.

Our lab previously showed that WS cell lines display a mitotic recombination resolution defect (Prince et al. (2001) Genes Dev. 15:933; Saintigny et al. (2002) Mol Cell Biol. 22:6971); and that the resolution functions of WRN require both its exonuclease and helicase activities (Swanson et al. (2004) DNA Repair 3:475).

My work has shown that the WS cell growth, DNA damage sensitivity, senescence and recombination phenotypes depend directly upon the loss of WRN protein function and can be revealed by acute short-hairpin RNA-mediated depletion of WRN protein. These phenotypes are observed in primary and SV40-transformed human fibroblasts. Also, I am analyzing cell growth, DNA damage sensitivity, senescence and recombination phenotypes of ear and embryonic fibroblasts from WRN-/- mice to determine if lack of WRN protein in mice results in WS-like cellular phenotypes.

Additionally, I am investigating whether BLM, another RecQ helicase that is implicated in Bloom syndrome (BS), and WRN have redundant functions in homologous recombination. These analyses are carried out in parallel in human and mouse fibroblasts that are deficient in one or both proteins and have an integrated direct-repeat recombination reporter.