skip to content

MRC Cancer Unit


Ashok VenkitaramanProfessor Ashok Venkitaraman

The Ursula Zoellner Professor of Cancer Research

Biography | Pubmed



Chomosomal instability in cancer pathogenesis and treatment

Cancer will affect 1 in every 3 people at some stage in their lives, making it a frequent cause of illness and death in every country in the world. Yet, looked at from a different perspective, one might as well ask, 'Why is cancer so rare?' instead of 'Why is cancer so common?' The human body comprises many trillions of cells, any one of which could potentially accumulate genetic alterations that lead to carcinogenesis. That this seldom occurs is testament to the efficiency of a network of cellular machines that preserve the integrity of the human genome, particularly during cell division

Chromosomal aberrations (top) occur when pathways for DNA recombination (bottom) are defective. Top panel from Patel, et al. (1998) Mol Cell 1, 347-357. Bottom panel from Venkitaraman (2003) N Engl J Med 348, 1917-1919.

We study this network not only to understand its physiology, but also to better define the earliest events that lead to cancer. One major interest is in exploring human genetic diseases in which the instability of chromosome structure or number is linked with predisposition to common types of cancer. This is complemented by a range of fundamental studies on DNA repair, replication and mitosis relevant to genome stability and cancer. For example, we have defined functions of the breast cancer susceptibility protein BRCA2 in the repair of replication-associated DNA lesions by homologous recombination mediated by the enzyme RAD51, discovered a role in the initiation of DNA replication for the Rothmund-Thomson syndrome helicase, RECQL4, and demonstrated how frequent amplification of the Aurora-A kinase in human cancers mis-regulates the machinery for chromosome segregation.

Our focus is on understanding the biological mechanisms that are relevant to disease pathogenesis, and on exploiting this understanding in new approaches to the therapy of the commonest human cancers. Therefore, our research spans a wide range of techniques from molecular cell biology to single-cell/single-molecule imaging to structural biology, biophysics and chemistry.

AURORA-A over-expression, which occurs  in 30-50% of common cancers, over-rides  the mitotic spindle assembly checkpoint  mediated by MAD2, allowing anaphase  entry with lagging chromosomes.  Aurora-A over-expressing cells (right) or  control cells (left)Our question-driven approach has led us to develop new experimental tools with wide application in several fields, and to a broad range of research interests relevant to genome stability and cancer. We have recently devised a general tool for conditional protein degradation in vertebrate cells, and used it to disable or reconstitute homologous recombination during different stages of the cell cycle, engendering a model in which homologous recombination during G2 is segregated from replication in S, and chromosome segregation, in M. We have combined biophysical microscopy with cell biology to identify a transient and rapid alteration in chromatin structure that precedes and permits phosphorylation of the variant histone, H2AX, defining a new signaling pathway that senses DNA breakage, and showing that chromatin structure can be changed during a physiological process via modification of a histone-code effector rather than the code itself.

One key goal of our work is to translate insights from fundamental research to improvements in the treatment of cancer. This has led to strong collaborations with colleagues in physics, chemistry and clinical medicine, besides pharma and biotech companies. We participate in the Cambridge Molecular Therapeutics Programme, a University-wide interdisciplinary initiative to pioneer approaches for the discovery and development of drugs against new types of molecular targets, as well as the Physics of Medicine programme.

These links support a range of ongoing projects in our laboratory that use interdisciplinary tools to investigate biological problems, and to create small molecules as tools for chemical biology and to seed the development of drugs.


Structure of a complex (top) between RAD51 (magenta/blue) and BRCA2 (green) predicts their possible functions in DNA recombination (bottom, from Venkitaraman (2002) Cell 108, 171-182).



Click here to contact Professor Ashok Venkitaraman by email.


Selected Publications:


Enhancing Biochemical Resolution by Hyperdimensional Imaging Microscopy. Esposito A, Venkitaraman AR. Biophys J. 2019 May 21;116(10):1815-1822. doi: 10.1016/j.bpj.2019.04.015. Epub 2019 Apr 22. PubMed PMID: 31060813; PubMed Central PMCID: PMC6531829.

Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling. Periasamy J, Kurdekar V, Jasti S, Nijaguna MB, Boggaram S, Hurakadli MA, Raina D, Kurup LM, Chintha C, Manjunath K, Goyal A, Sadasivam G, Bharatham K, Padigaru M, Potluri V, Venkitaraman AR. Cell Chem Biol.2018 Jun 21;25(6):677-690.e12. doi: 10.1016/j.chembiol.2018.02.012. Epub 2018 Mar 29. PubMed PMID: 29606576; PubMed Central PMCID: PMC6015222.

BRCA2 Regulates Transcription Elongation by RNA Polymerase II to Prevent R-Loop Accumulation. Shivji MKK, Renaudin X, Williams ÇH, Venkitaraman AR. Cell Rep. 2018 Jan 23;22(4):1031-1039. doi: 10.1016/j.celrep.2017.12.086. Epub 2018 Jan 28. PubMed PMID: 29386125.

Single-molecule localization microscopy reveals molecular transactions during RAD51 filament assembly at cellular DNA damage sites. Haas KT, Lee M, Esposito A, Venkitaraman AR. Nucleic Acids Res. 2018 Jan 4. doi:10.1093/nar/gkx1303. [Epub ahead of print] PubMed PMID: 29309696.

Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS. Narvaez AJ, Ber S, Crooks A, Emery A, Hardwick B, Guarino Almeida E, Huggins DJ, Perera D, Roberts-Thomson M, Azzarelli R, Hood FE, Prior IA, Walker DW, Boyce R, Boyle RG, Barker SP, Torrance CJ, McKenzie GJ, Venkitaraman AR. Cell Chem Biol. 2017 Aug 17;24(8):1017-1028.e7. doi:10.1016/j.chembiol.2017.07.009. Epub 2017 Aug 10. PubMed PMID: 28807782; PubMed Central PMCID: PMC5563081.

A Class of Environmental and Endogenous Toxins Induces BRCA2 Haploinsufficiency and Genome Instability.  Tan SLW, Chadha S, Liu Y, Gabasova E, Perera D, Ahmed K, Constantinou S, Renaudin X, Lee M, Aebersold R, Venkitaraman AR. Cell (2017) Jun 1;169(6):1105-1118.e15. doi: 10.1016/j.cell.2017.05.010. PubMed PMID: 28575672; PubMed Central PMCID: PMC5457488.

High-resolution structure of the presynaptic RAD51 filament on single-stranded DNA by electron cryo-microscopy.Short JM, Liu Y, Chen S, Soni N, Madhusudhan MS, Shivji MK, Venkitaraman AR. Nucleic Acids Res. (2016) Nov 2;44(19):9017-9030. Epub 2016 Sep 5. PubMed PMID: 27596592; PubMed Central PMCID: PMC5100573.

Regulation of constitutive and alternative mRNA splicing across the human transcriptome by PRPF8 is determinedby 5' splice site strength. Wickramasinghe VO, Gonzàlez-Porta M, Perera D, Bartolozzi AR, Sibley CR, Hallegger M, Ule J, Marioni JC, Venkitaraman AR. Genome Biol. (2015) Sep 21;16:201. doi: 10.1186/s13059-015-0749-3. PubMed PMID: 26392272; PubMed Central PMCID: PMC4578845.

Cancer suppression by the chromosome custodians, BRCA1 and BRCA2.Venkitaraman, A.R. Science (2014) 343(6178):1470-5.

Homeostatic control of polo-like kinase-1 engenders non-genetic heterogeneity in G2 checkpoint fidelity and timing. Liang H, Esposito A, De S, Ber S, Collin P, Surana U, Venkitaraman AR. Nature Commun (2014) 5:4048.

Diversity-oriented synthesis as a tool for identifying new modulators of mitosis. Ibbeson B.M., Laraia L., Alza E, O' Connor C.J., Tan Y., Davies H.M., McKenzie G., Venkitaraman A.R.*, Spring D.* Nature Commun. (2014) 5:3155.

A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization. Jeyasekharan, A.D., Liu, Y., Hattori, H., Pisupati, V., Jonsdottir, A.B., Rajendra, E., Lee, M., Sundaramoorthy, E., Schlachter, S., Kaminski, C., Rosenfeld, Y., Sato, K., Savill, J., Ayoub, N.& Venkitaraman, A.R. Nature Str Mol Biol. (2013). 20, 1191-8.

Human inositol polyphosphate kinase regulates transcript-selective nuclear mRNA export to preserve genome integrity.Wickramasinghe, V., Savill, J. Chavali, S., Jonsdottir, A.B., Rajendra, E., Gruner, T., Laskey, R., Babu, M., & Venkitaraman, A.R. (2013). Molecular Cell. 51, 737-43.

Continuous polo-like kinase 1 activity regulates diffusion to maintain centrosome self-organization during mitosis. Mahen, R., Jeyasekharan, A.D., Barry, N.P., and Venkitaraman, A.R. Proc Natl Acad Sci (2011). USA 108, 9310-9315.

Germline BRCA2 heterozygosity promotes KrasG12D–driven carcinogenesis in a murine model of familial pancreatic cancer.Skoulidis, F., Cassidy, L., Pisupati, V., Jonasson, J., Eyfjord, J., Kerreth, F., Lim, M., Olive, K. Tuveson, D. & Venkitaraman, A. R. Cancer Cell (2010) 18, 499-509.

The BRC repeats of human BRCA2 differentially regulate RAD51 binding on single- versus double-stranded DNA to stimulate strand exchange. Shivji, M. K., Mukund, S. R., Rajendra, E., Chen, S., Short, J. M., Savill, J., Klenerman, D., and Venkitaraman, A. R. Proc Natl Acad Sci USA (2009). 106, 13254-13259

UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit. Garnett, M., Mansfeld, J., Godwin, C., Matsusaka, T., Wu, J., Russell, P., Pines, J. & Venkitaraman, A. R. Nature Cell Biol (2009). 11, 1363-69.

HP1-beta mobilization promotes chromatin changes that initiate the DNA damage response. Ayoub N.A., A.D. Devaprasath, J.A. Bernal & A.R. Venkitaraman Nature (2008). 453: 682-6.