Month: April 2016
Dr Cesare’s laboratory has postdoctoral positions, fully funded for three years, starting in late 2016 or early 2017. We are in search of exceptional young scientists, interested in pursuing research on telomeres and genome stability. Opportunities exist in my lab for post-doctoral scientists to investigate:
1) the interplay between genomic DNA replication stress, or DNA damage, and telomere deprotection
2) mechanisms of telomere deprotection during ageing and in cancer
3) telomere biology in mitosis
4) mitotic chromosome dynamics
5) post-translational modifications in telomere deprotection signalling
6) nuclear architecture in the DNA damage response
Ideal candidates will be hard working, independent, and creative in their experimental approach. I also welcome candidates with established excellence in CRISPR/Cas9 mediated gene-editing, quantitative microscopy and/or automated imaging analysis, super-resolution microscopy, proteomics, ChIP-seq and RNA-seq.
Dr Cesare’s is located at the Children’s Medical Research Institute (CMRI) in Sydney, Australia. CMRI is home to the highest concentration of telomere research labs at a…
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A defining feature in over 2/3rds of all solid tumours is the continual loss and gain of whole are small parts of chromosomes. This instability, or CIN for short, strongly implicated in tumour initiation, progression, chemoresistance and poor prognosis. CIN is created through failures during mitosis, whereby whole or parts of a chromosome are segregated incorrectly, thereby created daughter cells with unequal chromosome numbers. Consequently, understanding how mitosis is regulated is essential for uncovering the mechanisms allowing CIN to arise and drive cancer. In our recent publication, we discovered the mechanisms controlling the key regulatory pathway critical to ensuring cells exit mitosis correctly. At the centre of this pathway is a gene call MASTL (short for ‘Microtubule Associated Serine/Threonine Kinase-Like’). The primary function of MASTL is to ensure that the cellular breaks (the phosphatase PP2A), is turned off during mitosis so that the accelerator (Cdk1 kinase) can drive the cell into mitosis. Much like a car, having the accelerator and breaks on at the same time is a bad idea, unless you like the smell of burning rubber. To successfully exit mitosis, and to perfectly segregate chromosomes, the cell must take the foot off the accelerator and turn on the breaks. Because MASTL is the central regulator ensuring the breaks are coordinated with the accelerator, it is essential to understand how MASTL is controlled. To this end, we uncovered that MASTL must be rapidly turned off to allow cells to exit mitosis, and this inactivation is carried out by another cellular brake call PP1 phosphatase (Rogers et al, JCS 2016). Now that we have identified and mapped this novel mitotic exit switch, we hope to be able to shed new light on how CIN drives the initiation and evolution cancer. We believe that with further study we will be able to better predict patient response to chemotherapy, and also identify new ways to ‘switch off’ highly unstable tumours, thereby improving treatment for patients that currently have a very poor prognosis.
Image of Interphase HeLa cell stained for Actin (red), DNA (blue) and the co-localisation of MASTL and PP1 by Proximity Ligation Assay (PLA; green).
Credit: Sam Rogers and Cell Division Lab