Page 379 - 2014 Printable Abstract Book
P. 379
(PS7-45) Proteinogenic amino acids alanine, glycine, and proline: calculation of xps chemical shifts.
Iogann Tolbatov and Daniel M. Chipman, University of Notre Dame, Radiation Laboratory, Notre Dame,
IN
Biomolecules are very sensitive to ionizing radiation. It induces damage in biomolecules as well
as chemical transformations of functional groups. Thus, it turns out to be a fundamental problem for
biology, medicine and for their practical applications (methods of radiation protection). X-ray
photoelectron spectroscopy (XPS) is a valuable tool in this area of research and is widely used for the
analysis of the radiation-induced chemical modifications in biomolecules. To facilitate analysis of such
photoelectron spectra, we have started a project focusing on establishing methods having potential to
improve analysis of experimental X-ray photoelectron spectra of amino acids, large polypeptides, and DNA
nucleosides in various environments by accurately calculating the XPS chemical shifts. We use the delta-
SCF approach and the Maximum Overlap Method to prevent variational collapse of the final whole state
in present study. We have analyzed a number of pure and hybrid density functionals of seven categories:
HF, LSDA, GGA, hybrid GGA, meta GGA, meta GGA hybrid, and range or asymptotically corrected
functionals. Also, we have evaluated performance of various standard and customized Pople, Dunning,
Ahlrichs basis sets and several exotic ones. The selected methodologies have been tested for the CEBE
calculations on selected proteinogenic amino acids: alanine, glycine, and proline. Computed results have
been compared with the experimental data, and the conclusions on the appropriateness of this method
were drawn.
(PS7-46) Ptch1 mutations and sonic hedgehog pathway deregulation impairs specifically base excision
1
3
2
1
repair in gorlin’s fibroblasts. Walid Rachidi ; Aurélie CHARAZAC ; Michele Martin ; and Thierry Douki
3
2
1
Univ. Grenoble Alpes, Grenoble, France ; CEA, Evry, France ; and CEA, Grenoble, France
The nevoid basal cell carcinoma syndrome (NBCCS), also called Gorlin syndrome is an autosomal
dominant disorder whose incidence is estimated at about 1 per 60 000 individuals. It is characterized by
several developmental abnormalities, radiosensitivity and an increased predisposition to the
development of basal cell carcinomas (BCCs). Mutations in the tumor suppressor gene PTCH1, which is
part of the Sonic Hedgehog (SHH) signaling pathway, are responsible for these clinical manifestations. As
several genetic mutations in the DNA repair genes are responsible of photo or radiosensitivity and high
predisposition to cancers, we hypothesized that these effects in Gorlin syndrome might be due to a defect
in the DNA damage response (DDR) and/or the DNA repair capacities. Therefore, the objective of this work
is to study the effect of PTCH1 mutations on the DNA damage response in order to better understand the
cellular and molecular mechanisms leading to hyper-radiosensitivity and high susceptibility to various
cancers in Gorlin’s patients. To that aim, we used fibroblasts from Gorlin patients or healthy individuals
and compared their radiosensitivity, their resistance to several stresses, the extent of DNA damage, the
expression of base excision repair (BER) genes and the corresponding enzymatic activity. Gorlin’s
fibroblasts showed high radiosensitivity upon exposure to ionizing radiation and also less resistance to
oxidative stress agents when compared to controls. However, no difference in cell viability was shown
after exposure to UVB or bleomycin. As BER is responsible for the repair of oxidative DNA damage, we
decided to assess the BER mechanisms in Gorlin’s fibroblasts. Interestingly, the levels of both BER gene
expression and BER protein activity were drastically decreased in Gorlin’s fibroblasts with respect to
controls. Our results suggest that PTCH1 mutation in Gorlin’s fibroblasts does not only impairs the BER
377 | P a g e
Iogann Tolbatov and Daniel M. Chipman, University of Notre Dame, Radiation Laboratory, Notre Dame,
IN
Biomolecules are very sensitive to ionizing radiation. It induces damage in biomolecules as well
as chemical transformations of functional groups. Thus, it turns out to be a fundamental problem for
biology, medicine and for their practical applications (methods of radiation protection). X-ray
photoelectron spectroscopy (XPS) is a valuable tool in this area of research and is widely used for the
analysis of the radiation-induced chemical modifications in biomolecules. To facilitate analysis of such
photoelectron spectra, we have started a project focusing on establishing methods having potential to
improve analysis of experimental X-ray photoelectron spectra of amino acids, large polypeptides, and DNA
nucleosides in various environments by accurately calculating the XPS chemical shifts. We use the delta-
SCF approach and the Maximum Overlap Method to prevent variational collapse of the final whole state
in present study. We have analyzed a number of pure and hybrid density functionals of seven categories:
HF, LSDA, GGA, hybrid GGA, meta GGA, meta GGA hybrid, and range or asymptotically corrected
functionals. Also, we have evaluated performance of various standard and customized Pople, Dunning,
Ahlrichs basis sets and several exotic ones. The selected methodologies have been tested for the CEBE
calculations on selected proteinogenic amino acids: alanine, glycine, and proline. Computed results have
been compared with the experimental data, and the conclusions on the appropriateness of this method
were drawn.
(PS7-46) Ptch1 mutations and sonic hedgehog pathway deregulation impairs specifically base excision
1
3
2
1
repair in gorlin’s fibroblasts. Walid Rachidi ; Aurélie CHARAZAC ; Michele Martin ; and Thierry Douki
3
2
1
Univ. Grenoble Alpes, Grenoble, France ; CEA, Evry, France ; and CEA, Grenoble, France
The nevoid basal cell carcinoma syndrome (NBCCS), also called Gorlin syndrome is an autosomal
dominant disorder whose incidence is estimated at about 1 per 60 000 individuals. It is characterized by
several developmental abnormalities, radiosensitivity and an increased predisposition to the
development of basal cell carcinomas (BCCs). Mutations in the tumor suppressor gene PTCH1, which is
part of the Sonic Hedgehog (SHH) signaling pathway, are responsible for these clinical manifestations. As
several genetic mutations in the DNA repair genes are responsible of photo or radiosensitivity and high
predisposition to cancers, we hypothesized that these effects in Gorlin syndrome might be due to a defect
in the DNA damage response (DDR) and/or the DNA repair capacities. Therefore, the objective of this work
is to study the effect of PTCH1 mutations on the DNA damage response in order to better understand the
cellular and molecular mechanisms leading to hyper-radiosensitivity and high susceptibility to various
cancers in Gorlin’s patients. To that aim, we used fibroblasts from Gorlin patients or healthy individuals
and compared their radiosensitivity, their resistance to several stresses, the extent of DNA damage, the
expression of base excision repair (BER) genes and the corresponding enzymatic activity. Gorlin’s
fibroblasts showed high radiosensitivity upon exposure to ionizing radiation and also less resistance to
oxidative stress agents when compared to controls. However, no difference in cell viability was shown
after exposure to UVB or bleomycin. As BER is responsible for the repair of oxidative DNA damage, we
decided to assess the BER mechanisms in Gorlin’s fibroblasts. Interestingly, the levels of both BER gene
expression and BER protein activity were drastically decreased in Gorlin’s fibroblasts with respect to
controls. Our results suggest that PTCH1 mutation in Gorlin’s fibroblasts does not only impairs the BER
377 | P a g e
