Abstract

The overall objective of this research proposal is to understand DNA mismatch repair of mammalian cells. The Principal Investigator proposes to define the roles and relationships of four mismatch repair protein homologs, hMSH2, hMLH1, hPMS1, and hPMS2. Also, he plans to identify additional proteins required for mismatch repair. Finally, the Principal Investigator proposes to identify other processes that either cooperate or interact with DNA mismatch repair to help maintain genetic stability.
Specific aims will include studying physical interactions among the four human proteins hMLH1, hPMS1, hPMS2, hMSH2 that are likely to be involved in the early steps of DNA mismatch repair. Portions or domains of the proteins which are responsible for protein-protein interactions will be defined. Both in vitro and in vivo approaches will be used. A second specific aim will be to use the yeast """"""""two hybrid"""""""" system to isolate new DNA mismatch repair genes. Studies should also identify other processes or pathways that interact with DNA mismatch repair. An attempt will be made to develop antibodies against the hMLH1 and hPMS2 proteins to study their cellular localization. The use of these antibodies in diagnostic studies will also be explored.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM045413-10
Application #
6180183
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Anderson, Richard A
Project Start
1991-04-01
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
10
Fiscal Year
2000
Total Cost
$232,226
Indirect Cost

  Institution

Name
Oregon Health and Science University
Department
Genetics
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239

  Publications

Johnson, Jennifer R; Erdeniz, Naz; Nguyen, Megan et al. (2010) Conservation of functional asymmetry in the mammalian MutL? ATPase. DNA Repair (Amst) 9:1209-13
Liskay, R Michael; Wheeler, Linda J; Mathews, Christopher K et al. (2007) Involvement of deoxycytidylate deaminase in the response to S(n)1-type methylation DNA damage in budding yeast. Curr Biol 17:R755-7
Tran, Phuoc T; Fey, Julien P; Erdeniz, Naz et al. (2007) A mutation in EXO1 defines separable roles in DNA mismatch repair and post-replication repair. DNA Repair (Amst) 6:1572-83
Erdeniz, Naz; Nguyen, Megan; Deschenes, Suzanne M et al. (2007) Mutations affecting a putative MutLalpha endonuclease motif impact multiple mismatch repair functions. DNA Repair (Amst) 6:1463-70
Deschenes, Suzanne M; Tomer, Guy; Nguyen, Megan et al. (2007) The E705K mutation in hPMS2 exerts recessive, not dominant, effects on mismatch repair. Cancer Lett 249:148-56
Mohd, Azizah B; Palama, Brett; Nelson, Scott E et al. (2006) Truncation of the C-terminus of human MLH1 blocks intracellular stabilization of PMS2 and disrupts DNA mismatch repair. DNA Repair (Amst) 5:347-61
Hegan, Denise Campisi; Narayanan, Latha; Jirik, Frank R et al. (2006) Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6. Carcinogenesis 27:2402-8
Gibson, Shannon L; Narayanan, Latha; Hegan, Denise Campisi et al. (2006) Overexpression of the DNA mismatch repair factor, PMS2, confers hypermutability and DNA damage tolerance. Cancer Lett 244:195-202
Erdeniz, Naz; Dudley, Sandra; Gealy, Regan et al. (2005) Novel PMS1 alleles preferentially affect the repair of primer strand loops during DNA replication. Mol Cell Biol 25:9221-31
Chen, Peng-Chieh; Dudley, Sandra; Hagen, Wayne et al. (2005) Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse. Cancer Res 65:8662-70

Showing the most recent 10 out of 31 publications