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DNA replication and repair mechanisms in cancer pathogenesis and therapy

How the cellular machineries that mediate DNA replication and repair cooperate to preserve the integrity of chromosome structure is poorly understood. Defects in these mechanisms not only predispose to cancer, but also profoundly affect the therapeutic response of the great majority of patients with advanced epithelial malignancies, who will receive treatment with radiation or DNA-damaging chemotherapeutic agents including radiomimetics and DNA cross-linking agents.

We have taken a number of different approaches to address these issues. For example, we have identified a new role for the DNA helicase mutated in Rothmund-Thomson syndrome in the initiation of DNA replication, connecting defective initiation with chromosomal instability and cancer predisposition in humans. 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.

Dissecting the regulation of DNA replication and repair using imaging, conditional genetics and cell biology.

Selected Publications:

Regulation of constitutive and alternative mRNA splicing across the human transcriptome by PRPF8 is determined by 5’ splice site strength. Wickramasinghe VO, Ganzalez-Porta M, Bartolozzi AR, Sibley CR, Hallegger M, Ule J, Marioni JC, Venkitaraman AR. Genome Biol. 2015 Sept 21; 16(1):201. PMID: 26392272

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.

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. Molecular Cell. (2013). 51, 737-43.

p53 shapes genome-wide and cell type-specific changes in microRNA expression during the human DNA damage response.Hattori H, Janky R, Nietfeld W, Aerts S, Madan Babu M, Venkitaraman AR. Cell Cycle. 2014;13(16):2572-86. doi: 10.4161/15384101.2015.942209

Modifying chromatin architecture during the response to DNA breakage.Venkitaraman AR. Crit Rev Biochem Mol Biol. 2010 Feb;45(1):2-13.

Mobilization and recruitment of HP1: a bimodal response to DNA breakage. Ayoub N, Jeyasekharan AD, Venkitaraman AR. Cell Cycle. 2009 Sep 15;8(18):2945-50.

Cell-cycle coordination between DNA replication and recombination revealed by a vertebrate N-end rule degron-Rad51. Su X, Bernal JA, Venkitaraman AR. Nat Struct Mol Biol. 2008 Oct;15(10):1049-58.

HP1-beta mobilization promotes chromatin changes that initiate the DNA damage response. Ayoub N, Jeyasekharan AD, Bernal JA, Venkitaraman AR. Nature. 2008 May 29;453(7195):682-6.

A FancD2-monoubiquitin fusion reveals hidden functions of Fanconi anemia core complex in DNA repair. Matsushita N, Kitao H, Ishiai M, Nagashima N, Hirano S, Okawa K, Ohta T, Yu DS, McHugh PJ, Hickson ID, Venkitaraman AR, Kurumizaka H, Takata M. Mol Cell. 2005 Sep 16;19(6):841-7.

Initiation of DNA replication requires the RECQL4 protein mutated in Rothmund-Thomson syndrome. Sangrithi MN, Bernal JA, Madine M, Philpott A, Lee J, Dunphy WG, Venkitaraman AR. Cell. 2005 Jun 17;121(6):887-98.

Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein. Lomonosov M, Anand S, Sangrithi M, Davies R, Venkitaraman AR. Genes Dev. 2003 Dec 15;17(24):3017-22.