hSSB1 Mutations in Cancer

Overview

Topic status: We're looking for students to study this topic.

The work proposed in this application focuses on the analysis of the DNA damage response pathway in human cells. This DNA damage response pathway is a crucial component of the surveillance network that maintains stability and integrity of our genome. Maintenance of genomic stability is critical for cellular homeostasis, with genomic instability leading to cancer or cell death. The ATM-dependent DNA Damage Response Pathway is specific for alteration in chromatin induced by one particular form of DNA lesion, DNA double-strand breaks (DSBs), that may be caused by normal genomic transactions such as meiotic recombination and the maturation of the immune system genes via V(D)J recombination, the cell's own metabolic environment (e.g hydrolysis and oxidation of DNA by endogenously generated reactive oxygen), error prone internal machinery (e.g. replication fork collapse), or may be due to exogenous agents such as ionizing radiation (IR), and certain chemotherapeutic drugs (1,2).

Our group recently identified two new players in the DSB repair pathway (Richard et al., Nature 2008). hSSB1 is highly over expressed in >90% of breast cancers. It is known that DNA damage proteins are often mutated in cancers (BRCA1, BRCA2, P53, PTEN etc). We aim to determine if hSSB1 or hSSB2 are mutated in breast cancers and determine the functional consequences of those mutations.

Hypothesis: Genomic stability is critical to prevent cancer, yet we know that cancer cells adapt the DNA repair and signaling machinery to allow their rapid un-checked cell growth. This same DNA repair machinery is also key to allowing the genetic variation within the tumor environment, which can accelerate cell growth and allow drug resistance to occur. This project aims to determine if the hSSB1 and hSSB2 genes are mutated in breast cancer. It will then study these mutations to determine if they have functional relevance.

  • Aim 1: Sequence the genomic regions containing the hSSB1 and 2 genes
  • Aim 2: Analyse these mutations and determine the functional relevance of these using microscopy and biochemical assays

Methods and techniques that will be developed in the course of this project:

  • Cell culture, microscopy
  • SDS PAGE, immunoblot, immuno-precipitation
  • Gel retardation assays
  • PCR and DNA sequencing
References:
  1. Khanna, K.K. and Jackson, S.P. (2001) Nat Genet, 27, 247-254.
  2. Richard, D.J., Bolderson, E. and Khanna, K.K. (2009) Crit Rev Biochem Mol Biol, 1-19.
Study level
Honours
Supervisors
QUT External Dr Derek Richard (QIMR)
Organisational unit

Science and Engineering Faculty

Research area

Cell and Molecular Biosciences

Contact
Please contact the supervisor.