title: Clustered abasic lesions profoundly change the structure and stability of human telomeric G-quadruplexes.
abstract: Ionizing radiation produces clustered damage to DNA which is difficult to repair and thus more harmful than single lesions. Clustered lesions have only been investigated in dsDNA models. Introducing the term 'clustered damage to G-quadruplexes' we report here on the structural effects of multiple tetrahydrofuranyl abasic sites replacing loop adenines (A/AP) and tetrad guanines (G/AP) in quadruplexes formed by the human telomere d[AG3(TTAG3)3] (htel-22) and d[TAG3(TTAG3)3TT] (htel-25) in K+ solutions. Single to triple A/APs increased the population of parallel strands in their structures by stabilizing propeller type loops, shifting the antiparallel htel-22 into hybrid or parallel quadruplexes. In htel-25, the G/APs inhibited the formation of parallel strands and these adopted antiparallel topologies. Clustered G/AP and A/APs reduced the thermal stability of the wild-type htel-25. Depending on position, A/APs diminished or intensified the damaging effect of the G/APs. Taken together, clustered lesions can disrupt the topology and stability of the htel quadruplexes and restrict their conformational space. These in vitro results suggest that formation of clustered lesions in the chromosome capping structure can result in the unfolding of existing G-quadruplexes which can lead to telomere shortening.
authors.affiliation: Institute of Biophysics, Czech Academy of Sciences, v.v.i., Královopolská 135, CZ-612 65 Brno, Czech Republic.
authors.forename: Iva
authors.initials: I
authors.lastname: Kejnovská
authors.affiliation: Institute of Biophysics, Czech Academy of Sciences, v.v.i., Královopolská 135, CZ-612 65 Brno, Czech Republic.
authors.forename: Klára
authors.initials: K
authors.lastname: Bednárová
authors.affiliation: Institute of Biophysics, Czech Academy of Sciences, v.v.i., Královopolská 135, CZ-612 65 Brno, Czech Republic.
authors.forename: Daniel
authors.initials: D
authors.lastname: Renciuk
authors.affiliation: Institute of Biophysics, Czech Academy of Sciences, v.v.i., Královopolská 135, CZ-612 65 Brno, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Dvoráková
authors.affiliation: Institute of Biophysics, Czech Academy of Sciences, v.v.i., Královopolská 135, CZ-612 65 Brno, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Školáková
authors.affiliation: CEITEC-Central European Institute of Technology, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic.
authors.forename: Lukáš
authors.initials: L
authors.lastname: Trantírek
authors.affiliation: CEITEC-Central European Institute of Technology, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic.
authors.forename: Radovan
authors.initials: R
authors.lastname: Fiala
authors.affiliation: Institute of Biophysics, Czech Academy of Sciences, v.v.i., Královopolská 135, CZ-612 65 Brno, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Vorlícková
authors.affiliation: Rimstone Laboratory, RLI, Carlsbad, CA 92010, USA.
authors.forename: Janos
authors.initials: J
authors.lastname: Sagi
mesh_terms: D000225:Adenine / Q000737:chemistry*; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D005663:Furans / Q000737:chemistry*; D054856:G-Quadruplexes; D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009841:Oligonucleotides / Q000737:chemistry; D012996:Solutions; D016615:Telomere / Q000235:genetics / Q000648:ultrastructure*; D059506:Telomere Shortening
chemical_list: D005663:Furans; D009841:Oligonucleotides; D012996:Solutions; D004247:DNA; D000225:Adenine