TY - JOUR
T1 - Developing master keys to brain pathology, cancer and aging from the structural biology of proteins controlling reactive oxygen species and DNA repair
AU - Perry, J. J.P.
AU - Fan, L.
AU - Tainer, J. A.
N1 - Funding Information:
Research results and analyses from the Tainer laboratory presented in this review come from studies supported by U.S. National Institutes of Health grants CA104660 for RecQ studies, CA112093 for XPB analysis, CA92584 for studies on cellular DNA repair machines and AI022160 for pili and ROS.
PY - 2007/4/14
Y1 - 2007/4/14
N2 - This review is focused on proteins with key roles in pathways controlling either reactive oxygen species or DNA damage responses, both of which are essential for preserving the nervous system. An imbalance of reactive oxygen species or inappropriate DNA damage response likely causes mutational or cytotoxic outcomes, which may lead to cancer and/or aging phenotypes. Moreover, individuals with hereditary disorders in proteins of these cellular pathways have significant neurological abnormalities. Mutations in a superoxide dismutase, which removes oxygen free radicals, may cause the neurodegenerative disease amyotrophic lateral sclerosis. Additionally, DNA repair disorders that affect the brain to various extents include ataxia-telangiectasia-like disorder, Cockayne syndrome or Werner syndrome. Here, we highlight recent advances gained through structural biochemistry studies on enzymes linked to these disorders and other related enzymes acting within the same cellular pathways. We describe the current understanding of how these vital proteins coordinate chemical steps and integrate cellular signaling and response events. Significantly, these structural studies may provide a set of master keys to developing a unified understanding of the survival mechanisms utilized after insults by reactive oxygen species and genotoxic agents, and also provide a basis for developing an informed intervention in brain tumor and neurodegenerative disease progression.
AB - This review is focused on proteins with key roles in pathways controlling either reactive oxygen species or DNA damage responses, both of which are essential for preserving the nervous system. An imbalance of reactive oxygen species or inappropriate DNA damage response likely causes mutational or cytotoxic outcomes, which may lead to cancer and/or aging phenotypes. Moreover, individuals with hereditary disorders in proteins of these cellular pathways have significant neurological abnormalities. Mutations in a superoxide dismutase, which removes oxygen free radicals, may cause the neurodegenerative disease amyotrophic lateral sclerosis. Additionally, DNA repair disorders that affect the brain to various extents include ataxia-telangiectasia-like disorder, Cockayne syndrome or Werner syndrome. Here, we highlight recent advances gained through structural biochemistry studies on enzymes linked to these disorders and other related enzymes acting within the same cellular pathways. We describe the current understanding of how these vital proteins coordinate chemical steps and integrate cellular signaling and response events. Significantly, these structural studies may provide a set of master keys to developing a unified understanding of the survival mechanisms utilized after insults by reactive oxygen species and genotoxic agents, and also provide a basis for developing an informed intervention in brain tumor and neurodegenerative disease progression.
KW - Werner syndrome
KW - amyotrophic lateral sclerosis
KW - ataxia-telangiectasia-like disorder
KW - nitric oxide synthase
KW - superoxide dismutase
KW - xeroderma pigmentosum
UR - http://www.scopus.com/inward/record.url?scp=34247157961&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34247157961&partnerID=8YFLogxK
U2 - 10.1016/j.neuroscience.2006.10.045
DO - 10.1016/j.neuroscience.2006.10.045
M3 - Review article
C2 - 17174478
AN - SCOPUS:34247157961
SN - 0306-4522
VL - 145
SP - 1280
EP - 1299
JO - Neuroscience
JF - Neuroscience
IS - 4
ER -