Orna Cohen-Fix, Ph.D.


Cell cycle regulation and nuclear structure section

LMCB
CELL CYCLE REGULATION & NUCLEAR STRUCTURE SECTION
NIDDK, National Institutes of Health
Building 8 , Room 319
8 Center Dr.
Bethesda, MD 20814
Tel: 301-594-2184
Fax: 301-402-0053
Email: ornacf@helix.nih.gov

Orna Cohen-Fix, PhD

Education / Previous Training and Experience:
B.A., Tel-Aviv University, Israel, 1986
M.S., Weizmann Institute, Israel, 1989
Ph.D., Weizmann Institute, Israel, 1994
Post-doc, The Carnegie Institution of Washington, Baltimore MD, 1998


Research Statement:
My lab is interested in two areas of research: cell cycle regulation and nuclear architecture. The cell cycle studies are mainly conducted in budding yeast, a great experimental system in which genetic, biochemical, cytological and molecular biology methodologies can be combined easily and effectively. The nuclear architecture studies are conducted in both yeast and C. elegans, again using a wide range of methodologies, as listed above.

Cell cycle regulation:
Accurate chromosomes transmission from one generation to the next depends on the ability of the cell to coordinate the many processes that lead to mitosis. This is accomplished by regulatory mechanisms that ensure that late cell cycle events take place only after earlier ones have been successfully completed. Some of these regulatory mechanisms are known as "checkpoint pathways", and defects in these pathways can lead to developmental defects and cancer. One of the key players in cell cycle regulation is the mitotic regulator separase, known in yeast as the Esp1 protein. Esp1 is a protease that is involved in several mitotic processes including sister chromatid separation and mitotic exit. We are currently studying the events that lead to Esp1 activation, which must be tightly regulated to avoid premature mitotic progression, and we are pursing the poorly understood role of Esp1 in spindle function.

Nuclear architecture:
Many nuclear processes, including transcription, DNA replication and gene silencing, are functionally linked to nuclear structure. In an attempt to uncover proteins that contribute to nuclear structure and integrity we are searching for mutations or conditions that alter nuclear shape, in either yeast or C. elegans. Ultimately, we would like to understand how nuclear shape and structure contribute to nuclear function. We found that lipid biosynthesis plays an important role in maintaining nuclear shape in yeast and in C. elegans (see Campbell et al, and Golden et al, below). Based on our studies we proposed a model that links ER structure to nuclear shape (see Webster et al, below). We conducted a systematic RNAi screen in C. elegans, an automated microscopy screen in budding yeast and various other types of screens to identify additional genes and pathways that contribute to nuclear shape and function. We currently have a large number of genes that affect nuclear structure and these fall into various functional categories, some of which are quite surprising, such as RNA processing, ribosome biogenesis and protein transport. We are currently investigating the mechanisms by which these and other genes affect nuclear organization.

Lab Members:
Orna Cohen-Fix (ornacf@helix.nih.gov)
Micah Webster (Micah.Webster@nih.hhs.gov)
Daphna Joseph-Strauss (Daphna.Joseph-Strauss@nih.hhs.gov)
Ananth Bommakanti (ananth.bommakanti@nih.gov)
Brandon Lee (brandon.lee@nih.gov)
Mohammad Rahman (mohammad.rahman@nih.gov)
Ritesh Agnihothri (agnihothrirv@mail.nih.gov)


Selected Publications:

Images of cells with abnormal nuclear shape (from left): budding yeast carrying a mutation in the spo7 gene; C. elegans embryo in which lipin was downregulated; a mutant yeast strain that came out of a visual screen.
Images of cells with abnormal nuclear shape (from left): budding yeast carrying a mutation in the spo7 gene; C. elegans embryo in which lipin was downregulated; a mutant yeast strain that came out of a visual screen

Webster MT, McCaffery JM, Cohen-Fix O. Vesicle trafficking maintains nuclear shape in Saccharomyces cerevisiae during membrane proliferation. J Cell Biol. (2010) 191, 1079-88. [Full Text/Abstract]

Cohen-Fix O. Cell biology: Import and nuclear size. Nature (2010) 468, 513-6. [Full Text/Abstract]

Witkin KL, Friederichs JM, Cohen-Fix O, Jaspersen SL. Changes in the nuclear envelope environment affect spindle pole body duplication in Saccharomyces cerevisiae. Genetics (2010) 186, 867-83. [Full Text/Abstract]

Webster M, Witkin, K. L, Cohen-Fix, O. Sizing up the nucleus: nuclear shape, size and nuclear envelope assembly. J. Cell Sci. (2009). 122, 1970-1978 [Full Text/Abstract]

Golden A, Liu J, Cohen-Fix, O. Inactivation of the C. elegans homolog of lipin leads to endoplasmic reticulum disorganization and defects in nuclear envelope breakdown and reassembly. J. Cell Sci. (2009), 122, 1477-1486 [Full Text/Abstract]

Fearon P, Cohen-Fix O. The endoplasmic reticulum takes center stage in cell cycle regulation. Sci Signal 1:pe4, 2008. [Full Text/Abstract]

Martinez ED, Botos J, Dohoney KM, Geiman TM, Kolla SS, Olivera A, Qiu Y, Rayasam GV, Stavreva DA, Cohen-Fix O.  Falling off the academic bandwagon. Women are more likely to quit at the postdoc to principal investigator transition. EMBO Rep.  (8) 977-81, 2007 [Full Text/Abstract]

de Gramont A, Barbour L, Ross KE, Cohen-Fix O. The spindle midzone microtubule-associated proteins Ase1p and Cin8p affect the number and orientation of astral microtubules in Saccharomyces cerevisiae. Cell Cycle (6):1231-41, 2007. [Full Text/Abstract]

de Gramont A, Ganier O, Cohen-Fix O. Before and after the spindle assembly checkpoint- an APC/C point of view. Cell Cycle (5) :2168-71, 2006 [Full Text/Abstract]

Campbell JL, Lorenz A, Witkin KL, Hays T, Loidl J, Cohen-Fix O Yeast nuclear envelope subdomains with distinct abilities to resist membrane expansion. Mol Biol Cell (17): 1768-78, 2006. [Full Text/Abstract]

de Gramont A, Cohen-Fix O The many phases of anaphase. Trends Biochem Sci (30): 559-68, 2005. [Full Text/Abstract]

Ross KE, Cohen-Fix O A role for the FEAR pathway in nuclear positioning during anaphase. Dev Cell (6): 729-35, 2004. [Full Text/Abstract]

Ross KE, Cohen-Fix O Molecular biology: cohesins slip sliding away. Nature (430): 520-1, 2004. [Full Text/Abstract]

Sarin S, Ross KE, Boucher L, Green Y, Tyers M, Cohen-Fix O Uncovering novel cell cycle players through the inactivation of securin in budding yeast. Genetics (168): 1763-71, 2004. [Full Text/Abstract]

Golden A Cohen-Fix O Getting (chromosomes) loaded--a new role for timeless. Dev Cell (5): 7-9, 2003. [Full Text/Abstract]

Cohen-Fix O Meiosis: polo, FEAR and the art of dividing reductionally. Curr Biol (13): R603-5, 2003. [Full Text/Abstract]

Ross KE Cohen-Fix O Multitasking at mitotic exit. Nat Cell Biol (5): 188-90, 2003. [Full Text/Abstract]

Ross KE Cohen-Fix O The role of Cdh1p in maintaining genomic stability in budding yeast. Genetics (165): 489-503, 2003. [Full Text/Abstract]

Agarwal R Tang Z Yu H Cohen-Fix O Two distinct pathways for inhibiting pds1 ubiquitination in response to DNA damage. J Biol Chem (278): 45027-33, 2003. [Full Text/Abstract]

Campbell JL Cohen-Fix O Chromosome cohesion: ring around the sisters? Trends Biochem Sci (27): 492-5, 2002. [Full Text/Abstract]

Agarwal R Cohen-Fix O Mitotic regulation: the fine tuning of separase activity. Cell Cycle (1): 255-7, 2002. [Full Text/Abstract]

Agarwal R Cohen-Fix O Phosphorylation of the mitotic regulator Pds1/securin by Cdc28 is required for efficient nuclear localization of Esp1/separase. Genes Dev (16): 1371-82, 2002. [Full Text/Abstract]

Ross KE Cohen-Fix O Separase: a conserved protease separating more than just sisters. Trends Cell Biol (12): 1-3, 2002. [Full Text/Abstract]

Hilioti Z Chung YS Mochizuki Y Hardy CF Cohen-Fix O The anaphase inhibitor Pds1 binds to the APC/C-associated protein Cdc20 in a destruction box-dependent manner. Curr Biol (11): 1347-52, 2001. [Full Text/Abstract]

Cohen-Fix O The making and breaking of sister chromatid cohesion. Cell (106): 137-40, 2001. [Full Text/Abstract]

Cohen-Fix O Sister chromatid separation: falling apart at the seams. Curr Biol (10): R816-9, 2000. [Full Text/Abstract]

Cohen-Fix O Koshland D Pds1p of budding yeast has dual roles: inhibition of anaphase initiation and regulation of mitotic exit. Genes Dev (13): 1950-9, 1999. [Full Text/Abstract]

Farr KA Cohen-Fix O The metaphase to anaphase transition: a case of productive destruction. Eur J Biochem (263): 14-9, 1999. [Full Text/Abstract]

Cohen-Fix O Koshland D The anaphase inhibitor of Saccharomyces cerevisiae Pds1p is a target of the DNA damage checkpoint pathway. Proc Natl Acad Sci U S A (94): 14361-6, 1997. [Full Text/Abstract]

Cohen-Fix O Koshland D The metaphase-to-anaphase transition: avoiding a mid-life crisis. Curr Opin Cell Biol (9): 800-6, 1997. [Full Text/Abstract]

Cohen-Fix O Peters JM Kirschner MW Koshland D Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC-dependent degradation of the anaphase inhibitor Pds1p. Genes Dev (10): 3081-93, 1996. [Full Text/Abstract]



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