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Matthew O'Connell

  • PROFESSOR Oncological Sciences
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Education

  • PhD, University of Adelaide
    Genetics

  • University of Oxford

  • UMDNJ-Robert Wood Johnson Medical School

  • Imperial Cancer Research Fund

Awards

  • 2014 - 2014
    Edward J. Ronin Award
    Graduate School of Biomedical Sciences, ISMMS

  • 2011 - 2011
    Outstanding Teaching by a Faculty Award, Graduate School of Biological Sciences
    Mount Sinai School of Medicine

  • 2010 - 2010
    Excellence in Teaching Award, Institute of Medical Education
    Mount Sinai School of Medicine

  • 2000 - 2005
    Scholar of the Leukemia and Lymphoma Society

  • 1993 - 1996
    Special Fellowship of the Leukemia Society of America

  • 1989 - 1990
    Australian Postgraduate Priority Research Award

  • 1987 - 1989
    Commonwealth Postgraduate Research Award

  • 1986 - 1986
    Fisher Scholarship in Honors Genetics
    University of Adelaide

  • 1985 - 1985
    R. A. Fisher Prize in Genetics
    University of Adelaide

Research

Specific Clinical/Research Interest: Regulation of the cell cycle; control over genomic stability and chromosome dynamics; the design of novel strategies for anti-cancer therapies

Current Students: Kevin Barnum and Nagma Shah

Postdoctoral Fellows: Claudia Tapia-Alveal,, Kirstin Bass, Su-Jiun Lin

Research Associate: Cara Reynolds, Aaron Yeoh

Summary of Research Studies:
Perhaps the most fundamental process in biology is that by which one cell becomes two. Our research focuses on two related aspects of the biology that controls the integrity of the genome.

 

1. We study the control of the cell division cycle, and the signaling pathways (checkpoints) that respond to chromosomal damage and prevent cell cycle progression until that damage is repaired.

 

DNA damage checkpoints function throughout the cell cycle. Those working in G1 phase to prevent the replication of damaged DNA are almost invariably mutated or inactivated in cancers. These defects contribute not only to the instability of tumor cell genomes, but can also knock-out pro-apoptotic pathways, rendering tumors resistant to treatment. Those functioning in G2 phase to prevent commitment to mitosis are, however, virtually always intact and appear to be required for the viability of tumor cells that lack G1 checkpoints. Our research is geared to dissect the molecular and cell biology of G2 checkpoints, and aims to use this knowledge in the design and testing of targeted anti-cancer therapies. Taking genetic and genomic approaches, we utilize fission yeast as a gene and pathway discovery tool, and then apply this information to studies in human cells. We are currently focusing our efforts into: (1) the regulation and function of a checkpoint effector protein kinase, Chk1, informing its suitability as a target in anti-cancer therapy; and (2) the initiating events that modify lesions in DNA into structures that signal the checkpoint and can be repaired.

 

2. We are investigating how determinants of chromosome structure regulate chromosome segregation and DNA repair, with an emphasis on events that occur during DNA replication.

 

Chromosomes are highly dynamic structures. They undergo massive reorganization to enable DNA replication and chromosome segregation to occur. This is under the control of the DNA topoisomerases, and three related and interacting Structural Maintenance ofChromosomes (SMC) complexes known as cohesin, condensin and the Smc5/6 complex. Defects in the processes controlled by these enzymes are a potent inducer of chromosome segregation defects leading to changes in chromosome number (aneuploidy). Their function during DNA replication appears to be particularly important, where they control recombination to ensure a complete round of replication by overcoming obstacles that block polymerases, which is then followed by chromosome reorganization in preparation for mitosis.  With the importance of replication fidelity, cells have back-up mechanisms controlled by a multi-BRCT domain protein (Brc1/PTIP) and the post-replication repair (PRR) machinery. We are focusing our efforts to understanding how these various genome integrity determinants are integrated in time and space to ensure accurate replication and division of the genome.

 

Publications

Caparelli ML, O'Connell MJ. Regulatory motifs in Chk1. Cell Cycle 2013; 12: 916-922.

Kuntz K, O'Connell MJ. Initiation of DNA damage responses through XPG-related nucleases. The EMBO journal 2013; 32: 290-302.

Bass K, Murray JM, O'Connell MJ. Brc1-dependent recovery from replication stress. Journal of Cell Science 2012; 125: 2753-2764.

Wang Y, Kallgren SP, Reddy BD, Kuntz K, López-Maury L, Thompson J, Watt S, Ma C, Hou H, Shi Y, Yates JR, Bähler J, O'Connell MJ, Jia S. Histone H3 lysine 14 acetylation is required for activation of a DNA damage checkpoint in fission yeast. The Journal of biological chemistry 2012 Feb; 287(6).

Tapia-Alveal C, O'Connell MJ. Nse1-dependent recruitment of Smc5/6 to lesion-containing loci contributes to the repair defects of mutant complexes. Molecular biology of the cell 2011 Dec; 22(23).

Tapia-Alveal C, O'Connell MJ. Methods for studying checkpoint kinases - Chk1. Methods in molecular biology (Clifton, N.J.) 2011; 782.

Tapia-Alveal C, O'Connell MJ. Methods for studying the G2 DNA damage checkpoint in mammalian cells. Methods in molecular biology (Clifton, N.J.) 2011; 782.

Tapia-Alveal C, Outwin EA, Trempolec N, Dziadkowiec D, Murray JM, O'Connell MJ. SMC complexes and topoisomerase II work together so that sister chromatids can work apart. Cell cycle (Georgetown, Tex.) 2010 Jun; 9(11).

Calonge TM, Eshaghi M, Liu J, Ronai Z, O'Connell MJ. Transformation/transcription domain-associated protein (TRRAP)-mediated regulation of Wee1. Genetics 2010 May; 185(1).

Kuntz K, O'Connell MJ. The G(2) DNA damage checkpoint: could this ancient regulator be the Achilles heel of cancer?. Cancer biology & therapy 2009 Aug; 8(15).

Outwin EA, Irmisch A, Murray JM, O'Connell MJ. Smc5-Smc6-dependent removal of cohesin from mitotic chromosomes. Molecular and cellular biology 2009 Aug; 29(16).

Tapia-Alveal C, Calonge TM, O'Connell MJ. Regulation of chk1. Cell division 2009; 4.

Irmisch A, Ampatzidou E, Mizuno K, O'Connell MJ, Murray JM. Smc5/6 maintains stalled replication forks in a recombination-competent conformation. The EMBO journal 2009 Jan; 28(2).

Industry Relationships

Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.

Dr. O'Connell did not report having any of the following types of financial relationships with industry during 2013 and/or 2014: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.

Mount Sinai's faculty policies relating to faculty collaboration with industry are posted on our website at http://icahn.mssm.edu/about-us/services-and-resources/faculty-resources/handbooks-and-policies/faculty-handbook. Patients may wish to ask their physician about the activities they perform for companies.

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