Tri-nucleotide repeat (TNR) DNA sequences occur throughout the human genome and have an intrinsic propensity to expand during replication. Expansion of such sequences is known to result in several human diseases, including Huntington's disease, spinocerebellar ataxia, and myotonic dystrophy. Errors in several DNA metabolic pathways due to the nature of TNR sequences have been implicated as the cause for TNR expansion. One mechanism for TNR expansion involves errors in Okazaki fragment maturation. Normally, 5'-flap endonuclease (FEN-1) cleaves the single stranded 5'-flap DNA structures generated during lagging-strand DNA synthesis. However, when the flap contains a TNR sequence, the flap can fold into a hairpin structure that has been shown to inhibit FEN-1 cleavage of the flap structures. Therefore, the inability of FEN-1 to process TNR 5'-hairpin-flaps is proposed to be one cause of TNR expansion. FEN-1 has recently been shown in vivo to proc similarities in TNR hairpin flap and fork DNA structures, it is hypothesized that the FEN-1 /WRN complex processes TNR hairpin flap structures in vivo, thereby suppressing TNR expansions in mammals. This hypothesis is consistent with the observation that deletion of the yeast FEN-1 gene results in critique one a two orders of magnitude difference in the incidence of TNR expansions. Furthermore, it is hypothesized that the unique DNA binding properties of WRN guide FEN-1 activity to TNR hairpin flap sites in addition to stimulating catalytic activity. ? ? ? ????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA117236-03
Application #
7459899
Study Section
Special Emphasis Panel (ZRG1-F08-G (20))
Program Officer
Myrick, Dorkina C
Project Start
2006-06-26
Project End
2009-06-25
Budget Start
2008-06-26
Budget End
2009-06-25
Support Year
3
Fiscal Year
2008
Total Cost
$52,048
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Zheng, Li; Jia, Jia; Finger, L David et al. (2011) Functional regulation of FEN1 nuclease and its link to cancer. Nucleic Acids Res 39:781-94
Finger, L David; Blanchard, M Suzette; Theimer, Carla A et al. (2009) The 3'-flap pocket of human flap endonuclease 1 is critical for substrate binding and catalysis. J Biol Chem 284:22184-94
Guo, Zhigang; Chavez, Valerie; Singh, Purnima et al. (2008) Comprehensive mapping of the C-terminus of flap endonuclease-1 reveals distinct interaction sites for five proteins that represent different DNA replication and repair pathways. J Mol Biol 377:679-90