ATRX: characterisation of a novel player in DNA damage repair
To divide indefinitely, tumour cells must maintain the length of their chromosome ends (telomeres). In the majority of tumours this is facilitated through the up regulation of telomerase. 15% of cancers, however, achieve immortality via an alternative, telomerase-independent mechanism, the so-called ALT pathway. It has recently become evident that many paediatric cancers are associated with an active ALT pathway, including several soft tissue cancers and cancers of the central nervous system (1). One implication is that it may be beneficial to tailor treatments depending on the ALT status of the cancer.
The development of novel therapies has so far been limited by a poor understanding of the molecular details governing the ALT pathway. Importantly, large-scale genome sequencing of a variety of cancers has identified ALT associated mutations in the ATRX gene. Accumulating evidence suggests that ATRX may play a direct role in DNA repair, with ATRX known to localise to sites of DNA damage (2). Despite this, very little is known about the mechanistic role ATRX plays at DNA damage sites. The proposed project will aim to address this using a variety of systematic approaches, including live cell imaging techniques to assess the recruitment of factors to DNA damage sites in real time. Training will be provided in molecular and cell biology skills for functional analysis of proteins; genome editing (CRISPR-Cas9 based gene tagging and deletion); and ultra-resolution, confocal and widefield microscopy. Secondary supervision will be provided by Richard Gibbons and Peter McHugh. Funding for this project will be provided through a CRUK/MRC Oxford Institute for Radiation Oncology Studentship.
Lovejoy et al. Loss of ATRX, Genome Instability, and an Altered DNA Damage Response Are Hallmarks of the Alternative Lengthening of Telomeres Pathway. Plos Genet 7(8) e1002772
- Leung et al. Alpha thalassemia/mental retardation syndrome X-linked gene product ATRX is required for proper replication restart and cellular resistance to replication stress ., 2013. The Journal of Biological Chemistry 288(9) 6342-6350
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