Maja Tarailo

MAJA TARAILO- PhD DEFENSE

“Spindle Assembly Checkpoint and Chromosome Stability in Caenorhabditis elegans”

B.Sc. University of British Columbia, 2002
Monday, November 26, 2007, 12:30pm, Room 203, Graduate Student Centre

SUPERVISORY COMMITTEE

Dr. Ann Rose (Medical Genetics)
Dr. Steven Jones (Medical Genetics)
Dr. Don Riddle (Medical Genetics)
Dr. Michel Roberge (Biochemistry and Molecular Biology)

EXAMINING COMMITTEE

Chair: Dr. Young Moon (Reproductive and Developmental Sciences)
Supervisory Committee: Dr. Ann Rose, Research Supervisor (Medical Genetics), Dr. Steven Jones (Medical Genetics)
University Examiners: Dr. Philip Hieter (Medical Genetics), Dr. Hugh Brock (Zoology)
External Examiner: Dr. Bruce Bowerman, Institute of Molecular Biology. University of Oregon. Eugene, OR. USA

ABSTRACT

In many species, proper chromosome segregation is accomplished with the aid of a surveillance mechanism, the spindle assembly checkpoint. To identify the mechanisms involved in this process, the mutants that suppress or enhance the mdf-1(gk2)/MAD1 checkpoint lethality were characterized. The suppressors of mdf-1(gk2) fall into two classes. The major class of suppressors compensates for the loss of the checkpoint by delaying mitotic progression. This class includes two known suppressors and anaphase promoting complex/cyclosome (APC/C) components, emb-30/APC4 and fzy-1/CDC20, and four new such (suppressors of spindle checkpoint defect) genes. One of the new such genes was found to be an APC5-like gene not previously identified as a component of the APC/C in C. elegans. This analysis revealed that APC5 and APC10 genes have paralogs in the C. elegans genome. Furthermore, a class of suppressors was identified that does not delay mitotic progression. In mouse cells, mutations that result in defective apoptosis rescued the lethality associated with deletion of the Mad2 gene. The suppressor mutants were analyzed for the apoptotic response and the such-7(h1985) suppressor with normal anaphase onset was found to abrogate the DNA damage-induced apoptosis. Despite the defective apoptotic response in this suppressor, loss of apoptosis alone could not rescue the mdf-1 lethality in C. elegans, indicating that other processes affected by the such-7 mutation, could account for the rescue of mdf-1(gk2) lethality. The upstream components required for the genome stability would be recognized as enhancers of the mdf-1(gk2) lethality. In yeast, 79 genes were found to result in synthetic lethal phenotype with MAD1. Of the 21 non-essential putative C. elegans orthologs assayed, nine enhanced mdf-1(gk2) lethality. The enhancers have a specific effect on the SAC, since six of them enhanced the mdf-2(tm2910)/MAD2 lethality, three also enhanced the san-1(ok1580) lethality and none enhanced lethality in the kinetochore mutant him-10(e1511ts)/NUF2. In addition two interactions, hcp-1 and bub-3, were identified in C. elegans that are not conserved in yeast. This analysis also showed that HCP-1 and HCP-2, the two CENP-F-related proteins, have a non redundant role, since only the hcp-1(RNAi) enhances lethality of the SAC mutants.

PUBLICATIONS

Tarailo M, Tarailo S, and Rose A M, (2007) Synthetic Lethal Interactions Identify Phenotypic “Interologs” of the Spindle Assembly Checkpoint Components. Genetics (in press) accepted on September 27th, 2007 (22 pages)

Tarailo M, Kitagawa R, and Rose A M, (2007) Suppressors of spindle checkpoint defect (such) mutants identify new mdf-1/MAD1 interactors in Caenorhabditis elegans. Genetics 175(4): 1665-1679.

Yang Z, Lai K, Cheung I, Youds J, Tarailo M, Tarailo S, and Rose A, (2006). A mutational analysis of Caenorhabditis elegans in space. Mutation Research 601(1-2): 19-29.

SELECTED PRESENTATIONS

Tarailo M, and Rose A M, Spindle Assembly Checkpoint and Chromosome Stability in Caenorhabditis elegans. Talk given at the 3rd Vancouver Worm Research Meeting, University of British Columbia, October 2007.

Tarailo M, and Rose A M, such mutants bypass MAD and result in CIN. Talk given at the Seattle-Vancouver Area Worm Meeting, Fred Hutchinson Cancer Research Center, Seattle, USA April 2007.

Tarailo M, and Rose A M, such mutants bypass MDF-1/Mad1 requirement without delaying mitosis. Poster presented at the 16th International C. elegans Meeting, Los Angeles, California, June 2007.

Tarailo M, and Rose A M, Suppressors bypass the spindle checkpoint requirement without delaying progression through mitosis. Poster presented at the Cell Cycle Meeting, Cold Spring Harbor, New York, May 2006.

Tarailo M, and Rose A M, What can we learn from genetic interactions with the spindleassembly checkpoint component MDF-1? Poster presented at the 15th International C. elegans Meeting, Los Angeles, California, June 2005.

Tarailo M, and Rose A M, Functional Interactors of MDF-1, a spindle assembly checkpoint component in Caenorhabditis elegans, Poster presented at the West Coast Worm Meeting, Santa Barbara, California, August 2004.

Tarailo M, and Rose A M, Suppressors of Mdf-1, metaphase to anaphase checkpoint in Caenorhabditis elegans, Poster presented at the 14th International C.elegans Meeting, Los Angeles, California, June 2003.

GRADUATE STUDIES

Field of Study: Checkpoints and Chromosome Stability

Courses:

MEDG505: Genome Analysis, Drs. S. Jones & P. Hieter

MEDG520: Advanced Human Molecular Genetics, Dr. E. Simpson

MEDG540: Medical Genetics Seminar, Drs. F. Dill & C. Brown

MEDG530: Advanced Human Genetics, Dr. J. Friedman

BIOC435: Molecular Biology and Biochemistry of the Yeast Saccharomyces, Dr. I. Sadowski

MEDG548: Directed Studies, Dr. A. Rose

CREDENTIALS

2004 Canadian Bioinformatics Workshop Certificate

Maja Tarailo- PhD Defense program- pdf