Molecular Mechanisms of Genomic Instability at G/C-rich STR Sequences

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Short-tandem-repeat (STR) and/or minisatellites (MNs) are repetitive DNA sequences, comprising 5-100 bp tandem repeats, and are dispersed throughout the mammalian genome. Mutations in STR/MN are induced in mammalian culture cells when cells are treated with various DNA damaging agents and also a tumor promoter, okadaic acid [Nakagama, et al., Imai, et al.]. STR/MNs are frequently found to be mutated in tumors [Inamori, et al.]. However, the molecular mechanisms underlying the induction of STR/MN mutations are largely unknown. The minisatellite repeat (5'-GGGCA-3')n in the mouse STR/MN Pc-1 was found, by NMR and CD spectrum analyses, to form an intrastrand anti-parallel quadruplex (G4') [Katahira, et al.]. Since DNA polymerase progression in vitro is blocked at d(GGG) sites, the higher structure of these repeats could be partially responsible for the hypermutable feature of STR/MNs in vivo. Several STR/MN Pc-1 binding proteins have been isolated from a cultured mouse cell line, and their involvement in MN mutation is currently being investigated [Fukuda, et al., Tsuchiya, et al.,Tanaka, et al.]. One of those MN Pc-1 binding proteins, hnRNP A1/UP1, was demonstrated to unfold the intramolecular quadruplex structure of d(CAGGG)₄ and d(TTAGGG)₄ and to abrogate the arrest of DNA synthesis at a d(GGG) site [Fukuda, et al.]. hnRNP A1/UP1 was also indicated to unfold the peculiar higher DNA structure of the d(CGG) triplet repeat and to abrogate the arrest of DNA synthesis at the site[Fukuda, et al.]. These abilities of hnRNP A1/UP1 suggest that the protein play roles in stable maintenance of G-rich repetitive sequences, including STR, telomeres and triplet repeats [Nakagama, et al. ].


Intramolecular Quadruplex