Oxidative guanine base damage regulates human telomerase activity.
Changes in telomere length are associated with degenerative diseases and cancer. Oxidative stress and DNA damage have been linked to both positive and negative alterations in telomere length and integrity. Here we examined how the common oxidative lesion 8-oxo-7,8-dihydro-2'-deoxyguanine (8-oxoG) regulates telomere elongation by human telomerase. When 8-oxoG is present in the dNTP pool as 8-oxodGTP, telomerase utilization of the oxidized nucleotide during telomere extension is mutagenic and terminates further elongation. Depletion of MTH1, the enzyme that removes oxidized dNTPs, increases telomere dysfunction and cell death in telomerase-positive cancer cells with shortened telomeres. In contrast, a preexisting 8-oxoG within the telomeric DNA sequence promotes telomerase activity by destabilizing the G-quadruplex DNA structure. We show that the mechanism by which 8-oxoG arises in telomeres, either by insertion of oxidized nucleotides or by direct reaction with free radicals, dictates whether telomerase is inhibited or stimulated and thereby mediates the biological outcome.
Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Elise
E
Fouquerel
Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Justin
J
Lormand
Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Arindam
A
Bose
Department of Biophysics, Johns Hopkins University, Baltimore, MD, USA.
Hui-Ting
HT
Lee
Department of Bioengineering, University of Illinois, Urbana, IL, USA.
Grace S
http://orcid.org/0000-0003-3210-2098
GS
Kim
University of South Alabama Mitchell Cancer Institute, Mobile, AL, USA.
Jianfeng
J
Li
University of South Alabama Mitchell Cancer Institute, Mobile, AL, USA.
Robert W
http://orcid.org/0000-0001-7385-3563
RW
Sobol
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA.
Bret D
BD
Freudenthal
Department of Biophysics, Johns Hopkins University, Baltimore, MD, USA.|Department of Bioengineering, University of Illinois, Urbana, IL, USA.
Sua
S
Myong
Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.|Center for Nucleic Acids Science and Technology, Carnegie Mellon University, Pittsburgh, PA, USA.
Patricia L
PL
Opresko
D001483:Base Sequence; D016923:Cell Death; D002460:Cell Line; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D003848:Deoxyguanine Nucleotides / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D054856:G-Quadruplexes; D006801:Humans; D009153:Mutagens / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000737:chemistry / Q000378:metabolism*; D059506:Telomere Shortening
D018736:DNA Adducts; D003848:Deoxyguanine Nucleotides; D009153:Mutagens; C078206:8-oxodeoxyguanosine triphosphate; D004247:DNA; D019098:Telomerase