We study the signalling mechanisms cells use to respond to DNA damage and why defects in these pathways cause human diseases such as cancer.
Mutations caused by DNA damage enable a normal cell to become cancerous. This is highlighted by the fact that individuals with mutations in many genes involved in DNA damage recognition, signalling and repair are predisposed to cancer, and that somatically acquired defects in such genes can drive tumour formation. Furthermore, some of the most effective cancer treatments work in tumour cells by inducing DNA damage, particularly DNA double-strand breaks, which are especially toxic and difficult to repair accurately without introducing mutations. Exploiting knowledge of DNA double-strand break repair is therefore likely to lead to more effective and personalised cancer therapies and treatments for patients with DNA repair disorders in future.
The aim of our research is to gain a greater understanding of the signalling mechanisms cells use to coordinate DNA double-strand break recognition and repair with cell cycle checkpoint activation and apoptosis. To achieve this, we are using cutting-edge bioinformatics, proteomics, microscopy and CRISPR-Cas9 gene-editing techniques to answer specific questions related to DNA damage signalling. In doing so, we hope to provide novel insights into carcinogenesis and how it is held at bay by the cell’s DNA damage response system. We also aim to translate our research to develop novel potential cancer treatments. In particular, we are interested in the potential utility of signalling events for use as biomarkers and to identify novel targets in the DNA damage response for anti-cancer drugs.
A major focus of our work is trying to understand how the products of genes mutated in DNA repair and cancer predisposition disorders such as Bloom syndrome are regulated by post-translational modifications and protein-protein interactions. Patients with Bloom syndrome suffer from a variety of symptoms including growth retardation, immunodeficiency, hypersensitivity to sunlight in addition to cancer predisposition. It is caused by mutations in BLM, a DNA helicase that plays important roles in coordinating DNA double-strand break repair and recombination, particularly during DNA replication and mitosis. However, we still know little about how this protein is regulated during the repair process and throughout the cell cycle. We are addressing this question by characterising novel post-translational modifications and protein-protein interactions of BLM and its binding partners.
Andrew Blackford is a Group Leader within the CRUK/MRC Oxford Institute for Radiation Oncology and Department of Oncology, based at the Weatherall Institute of Molecular Medicine. After obtaining his PhD in the School of Cancer Sciences at the University of Birmingham in 2008, he undertook postdoctoral positions with Wojciech Niedzwiedz at the University of Oxford in 2009 and Steve Jackson in the Wellcome Trust/CRUK Gurdon Institute at the University of Cambridge in 2012. He was awarded a Cancer Research UK Career Development Fellowship and took up his current post in June 2016.
Sun L et al. (2017) Structural insight into BLM recognition by TopBP1. Structure 25, 1582-1588.
Blackford AN & Jackson SP (2017) ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol. Cell 66, 801-817.
Henssen AG et al. (2017) PGBD5 promotes site-specific oncogenic mutations in human tumors. Nat. Genet. 49, 1005-1014.
Balmus G et al. (2016) Synthetic lethality between PAXX and XLF in mammalian development. Genes Dev. 30, 2152-2157.
Lescale C et al. (2016) Specific roles of XRCC4 paralogs PAXX and XLF during V(D)J recombination. Cell Rep. 16, 2967-2979.
Blackford AN et al. (2015) TopBP1 interacts with BLM to maintain genome stability but is dispensable for preventing BLM degradation. Mol. Cell 57, 1133-1141.
Ochi T et al. (2015) PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair. Science 347, 185–188.
Polo SE et al. (2012) Regulation of DNA-end resection by hnRNPU-like proteins promotes DNA double-strand break signaling and repair. Mol. Cell 45, 505–516.
Blackford AN et al. (2010) Adenovirus 12 E4orf6 inhibits ATR activation by promoting TOPBP1 degradation. Proc. Natl. Acad. Sci. USA 107, 12251–12256.