Dr S.P. LEES-MILLER

Professor,  Departments of Biochemistry and Molecular Biology, Oncology and Biological Sciences

She holds a Scientist Award from the Alberta Heritage Foundation for Medical Research (AHFMR) and an Investigator Award from the Canadian Institutes of Health Research (CIHR). 

Affiliations: Alberta Cancer Foundation/Engineered Air Chair in Cancer Research.

Research Interests
The Lees-Miller lab studies how mammalian cells detect and repair DNA double strand breaks (DSBs). DSBs are caused by exogenous DNA damaging agents such as ionizing radiation (IR), reactive oxygen species (ROS) and topoisomerase poisons. They also occur as a consequence of natural cellular processes such as oxidative metabolism and V(D)J recombination. Cells that are unable to detect and/or repair DSBs are highly radiosensitive and exhibit genomic instability.

One of the major projects in the Lees-Miller lab is to understand the mechanism of Non Homologous End Joining (NHEJ), which is the major pathways for the repair of IR-induced DSBs in human cells. In particular we are interested in the role of the DNA-dependent protein kinase, DNA-PK, in this process.

A better understanding how cells detect and repair IR-induced DNA damage, could lead to the design of therapeutic agents to make cancer cells more sensitive to radiation-induced killing, leading to better treatments for cancer patients.

The Lees-Miller lab is grateful to the Alberta Heritage Foundation for Medical Research (AHFMR), the Alberta Cancer Board (ACB), the Canadian Institutes of Health Research (CIHR) and the National Cancer Institute of Canada (NCIC) for financial support.

Lab Web site

Personnel:

Lees-Miller and Cobb lab members on lab hike, Fall 2009:

View Pub Med for Recent publications & abstracts

Recent Publications:

• 1. Kim M, Williamson CT, Prudhomme J, Bebb DG, Riabowol K, Lee PWK, Lees-Miller SP, Mori Y, Rahman MM, McFadden G, Johnston RN.(2010) The viral tropism of two distinct oncolytic viruses, reovirus and myxoma virus, is modulated by cellular tumor suppressor gene status. Oncogene (in press)
• 1. Li A, Yu Y, Lee SC, Ishibashi T, Lees-Miller SP, Ausio J. Phosphorylation of histone H2A.X by DNA-dependent Protein Kinase (DNA-PK) is not affected by core histone acetylation but it alters nucleosome stability and histone H1 binding. J Biol Chem. 2010 Mar 31. [Epub ahead of print]
• 1. Douglas P, Zhong J, Ye R, Moorhead GB, Xu X, Lees-Miller SP. Protein phosphatase 6 interacts with the DNA-dependent protein kinase catalytic subunit and dephosphorylates gamma-H2AX. Mol Cell Biol. 2010 Mar;30(6):1368-81.
• 1. Williamson CT, Muzik H, Turhan AG, Zamò A, O'Connor MJ, Bebb DG, Lees-Miller SP. ATM deficiency sensitizes mantle cell lymphoma cells to poly(ADP-ribose) polymerase-1 inhibitors. Mol Cancer Ther. 2010 Feb;9(2):347-57.
• Hammel M, Yu Y, Mahaney BL, Cai B, Ye R, Phipps BM, Rambo RP, Hura GL, Pelikan M, So S, Abolfath RM, Chen DJ, Lees-Miller SP*, Tainer JA. (2010) Ku and DNA-dependent protein kinase (DNA-PK) dynamic conformations and assembly regulate DNA binding and the initial nonhomologous end joining complex. J. Biol. Chem. Epub ahead of print, accepted Nov 9 2009. * co-corresponding author.
• Mahaney BL, Meek K, Lees-Miller SP. (2009) Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining. Biochem J 417:639-650.
• Williams ES, Klingler R, Ponnaiya B, Hardt T, Schrock E, Lees-Miller SP, Meek K, Ullrich RL, Bailey SM.  (2009) Telomere dysfunction and DNA-PKcs deficiency: characterization and consequence. Cancer Res 69:2100-7.
• Akopiants K, Zhou RZ, Mohapatra S, Valerie K, Lees-Miller SP, Lee KJ, Chen DJ, Revy P, de Villartay JP, Povirk LF (2009) Requirement for XLF/Cernunnos in alignment-based gap filling by DNA polymerases lambda and mu for nonhomologous end joining in human whole-cell extracts. Nucleic Acids Res. 37(12):4055-62.
• Zhou T, Akopiants K, Mohapatra S, Lin PS, Valerie K, Ramsden DA, Lees-Miller SP, Povirk LF. Tyrosyl-DNA phosphodiesterase and the repair of 3'-phosphoglycolate-terminated DNA double-strand breaks.DNA Repair (Amst). 2009 Aug 6;8(8):901-11.
• Ting NS, Pohorelic B, Yu Y, Lees-Miller SP, Beattie TL (2009).The human telomerase RNA component, hTR, activates the DNA-dependent protein kinase to phosphorylate heterogeneous nuclear ribonucleoprotein A1. Nucleic Acids Res. 37(18):6105-15.
• Povirk LF, Zhou RZ, Ramsden DA, Lees-Miller SP, Valerie K. Phosphorylation in the serine/threonine 2609-2647 cluster promotes but is not essential for DNA-dependent protein kinase-mediated nonhomologous end joining in human whole-cell extracts. Nucleic Acids Res. 2007;35(12):3869-78.
• Lees-Miller SP. The double (strand break) life of Par-3. Nat Cell Biol. 2007 Apr;9(4):363-5.
• Shi L, Qiu D, Zhao G, Corthesy B, Lees-Miller S, Reeves WH, Kao PN. Dynamic binding of Ku80, Ku70 and NF90 to the IL-2 promoter in vivo in activated T-cells. Nucleic Acids Res. 2007;35(7):2302-10.
• Meek K, Douglas P, Cui X, Ding Q, Lees-Miller SP. trans Autophosphorylation at DNA-dependent protein kinase's two major autophosphorylation site clusters facilitates end processing but not end joining.  Mol Cell Biol. 2007 May;27(10):3881-90.
• Goodarzi AA, Douglas P, Moorhead GB, Lees-Miller SP. Utilizing protein phosphatase inhibitors to define PP2A as a regulator of ataxia-telangiectasia mutated. Methods Mol Biol. 2007;365:47-59.
• Douglas P, Cui X, Block WD, Yu Y, Gupta S, Ding Q, Ye R, Morrice N, Lees-Miller SP, Meek K. The DNA-dependent protein kinase catalytic subunit is phosphorylated in vivo on threonine 3950, a highly conserved amino acid in the protein kinase domain. Mol Cell Biol. 2007 Mar;27(5):1581-91.

Contact Information:

The University of Calgary
Room 2A22, Health Research Innovation Centre
3280 Hospital Drive NW, Calgary, Alberta
Canada T2N 4Z6
Phone (403) 220-7628
Fax: (403) 283-8727
E-mail: leesmill [at] ucalgary [dot] ca