Title

Grigory Dianov

Biochemistry and Regulation of DNA Repair Group

The long-term goal of the Dianov Laboratory is to study the proteins and mechanisms involved in the coordination and regulation of Base Excision Repair

Email: 
grigory.dianov@oncology.ox.ac.uk
Telephone: 
44 (0)1865 617325 / +44 (0)1865 617318 (PA)
PA: 
Helen Fanyinka
Email PA: 
helen.fanyinka@oncology.ox.ac.uk

Research Summary

Our research focuses on the study of the proteins and mechanisms involved in the co-ordination and regulation of Base Excision Repair (BER, Figure 1), to unravel their role in the repair of radiation-induced DNA damage and to examine the relationship to human diseases, such as cancer.

Figure 1: BER pathway.

BER is a frontline DNA repair system that is responsible for maintaining genome integrity, thus preventing many human diseases, including premature aging, cancer, and neurodegenerative diseases. It is estimated that through BER pathway a human cell repairs 10,000-20,000 DNA lesions every day. The majority of these lesions arise from the intrinsic chemical instability of DNA, resulting in DNA single strand beaks, hydrolytic loss of DNA bases, base oxidations, non-enzymatic methylations and other chemical alterations. BER is also the principal DNA repair system in cancer cells that counteracts the killing effect of the major cancer treatments, i.e. chemotherapy and ionizing radiation (approximately 80% of DNA damage induced by ionizing radiation are DNA base lesions).

Changes in BER capacity most probably are responsible for many cases of cancer treatment efficiency, since many cancers have altered expression of BER proteins. Although BER enzymes have been studied in detail, the mechanisms involved in BER coordination and regulation are unclear.

The Biochemistry Laboratory has identified a novel molecular mechanism that regulates expression of BER proteins and coordinates DNA repair with the cell cycle progression (Figure 2). These studies are providing new insight into the biochemistry and regulation of DNA repair and how they impact cancer development and progression.

Figure 2: BER regulation.

Biography

Professor Dianov came to the UK in 1990 and spent three years as a Senior Research Fellow at the Imperial Cancer Research Fund, Clare Hall Laboratories. From 1993 to 1995 Dr Dianov was a Visiting Associate Professor within the Department of Pathology at the University of Texas, USA and then joined the National Institute on Aging in Baltimore, USA. He returned to the UK in 2000 as a Senior Group Leader within the Radiation and Genome Stability Unit of the Medical Research Council, before coming to Oxford to lead the Biochemistry Laboratory within the Department of Oncology at the University of Oxford in 2007.

Publications

SELECTED PUBLICATIONS:

Khoronenkova SV, Dianova II, Ternette N, Kessler BM, Parsons JL, Dianov GL. ATM-Dependent Downregulation of USP7/HAUSP by PPM1G Activates p53 Response to DNA Damage. Mol Cell. 2012, 45:801-813

Parsons JL, Dianova II, Khoronenkova SV, Edelmann MJ, Kessler BM, Dianov GL. USP47 is a deubiquitylating enzyme that regulates base excision repair by controlling steady-state levels of DNA polymerase β. Mol Cell. 41:609-615, 2011

Poletto M, Legrand AJ, Fletcher SC and Dianov GL.  p53 coordinates base excision repair to prevent genomic instability. Nucleic Acids Research, 2016, 44:3165-3175.

Pfister SX, Markkanen E, Jiang Y, Sarkar S, Woodcock M, Orlando G, Mavrommati I, Pai CC, Zalmas LP, Drobnitzky N, Dianov GL, Verrill C, Macaulay VM, Ying S, La Thangue NB, D’Angiolella V, Ryan A and Humphrey TC. Inhibiting WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation. Cancer Cell, 2015, 28:557-568

Khoronenkova SV, Dianov GL.  p53 coordinates base excision repair to prevent genomic instability. Poletto M, Legrand AJ, Fletcher SC and Dianov GL. ATM prevents DSB formation by coordinating SSB repair and cell cycle progression. Proc Natl Acad Sci U S A. 2015, 112:3997-4002

Associated Researchers

Group Members

Siobhan Cunniffe, Laboratory Manager (joint with Professor Tom Brown)
Sally Fletcher, DPhil Student
Claudia Grou, Postdoctoral Researcher
Samuel Hume, MRes Student
Arnaud Legrand, Postdoctoral Researcher
Di Yang, DPhil Student (joint with Professor Tom Brown)

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