 |
Professor of Human Genetics; Professor of Pediatrics and Communicable Diseases |
|
| 4718A Med Sci II 1241 E. Catherine St. SPC 5618 Ann Arbor, MI 48109 -5618 |
||
Our research focuses on the areas of genome instability and the molecular biology of human genetic disease. A longstanding interest is the study of chromosomal fragile sites. These are chromosome loci that are especially sensitive to breakage following replication stress. Fragile sites, and associated genes, are frequently deleted or rearranged in many cancer cells. We are studying the molecular mechanisms responsible for this unusual instability as a model for the broader consequences of replication stress in mammalian cells. A key to our understanding was our discovery that that the ATR cell cycle checkpoint pathway is critical to genome stability at fragile sites. This was the first major molecular pathway involved in fragile site stability to be identified, and our findings have had broad implications for the consequence of stalled replication in mammalian cells. We have subsequently found that the BRCA1 gene and the genes responsible for Fanconi anemia also play roles in fragile site stability. Our current efforts are aimed at fully understanding the consequences of replication stress on the human genome and the related DNA replication and repair pathways that regulate chromosome stability at fragile sites and elsewhere in the genome.
A second interest is the study of hereditary lymphedema and lymphatic development. We identified a gene that is responsible for hereditary lymphedema-distichiasis syndrome, the FOXC2 forkhead-family transcription factor, and have also identified an ideal mouse model for study of the disorder. Little is known about the development of the complex lymphatic vascular system, and our findings provide a unique genetic link to these molecular and cellular pathways. Our studies include the developmental regulation of Foxc2 expression in vascular development and determining its downstream targets.
The third major interest is Hutchinson-Gilford Progeria (HGP). HGP is a disorder characterized by the premature onset of many of the features associated with aging, such as an aged appearance and arteriosclerosis, with death usually before age 15. We participated in a consortium effort that identified the gene (lamin A/C) responsible for this fascinating disorder, opening the door to current functional studies and possible treatments.
NIH New Investigator Award, 1985
NIH Shannon Award, 1991
March of Dimes Birth Defects Foundation Research Advisory Board 1998-2003
NIH, MGM/GHD Sections 1992, 1997, 1999 - 2001, 2005, 2006
Medical School Executive Committee, University of Michigan, Ann Arbor, MI 2002-2005
Distinguished Faculty Achievement Award, University of Michigan, 2005
Michigan State University, 1972 B.S.
Michigan State University, 1978 Ph.D.
Durkin SG, Ragland RL, Arlt FM, Mulle JG, Warren ST, Glover TW: Replication stress induces tumor-like microdeletions in FHIT/FRA3B. Proc Natl Acad Sci USA 105: 246-251, 2008.
Durkin SG, Glover TW: Chromosome fragile sites. Annual Review Genetics 41: 2007 Annu Rev Genet 41: 169-192, 2007.
Durkin SG, Arlt MF, Howlett NG, Glover TW: Depletion of CHK1, but not CHK2, induces chromosomal instability and breaks at common fragile sites. Oncogene 25: 4381-4388, 2006.
Glynn MW, Glover TW: Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Hum Mol Genet 14: 2959-2569, 2005.
Howlett NG, Taniguchi T, Durkin SG, D'Andrea AD, Glover TW: The Fanconi anemia pathway is required for the DNA replication stress response and for the regulation of common fragile site stability. Hum Mol Genet 14: 693-701, 2005
Arlt MF, Xu B, Durkin SG, Casper AM, Kastan MB, Glover TW: BRCA1 is required for common-fragile site-stability via its G2/M checkpoint function. Mol Cell Biol 24: 6701-6709, 2004
Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS: Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford Progeria Syndrome. Nature 423: 293-298, 2003
Casper AM, Nghiem P, Arlt MF, Glover TW: ATR regulates fragile site stability. Cell 111: 779-789, 2002.
Home