Genetic instabilities of (CCTG)·(CAGG) and (ATTCT)·(AGAAT) disease‐associated repeats reveal multiple pathways for repeat deletion

Edwards, Sharon F.; Hashem, Vera I.; Klysik, Elzbieta; Sinden, Richard R.

doi:10.1002/mc.20534

Cited by 14 publications

(11 citation statements)

References 75 publications

(149 reference statements)

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“…Plasmid pBR325 provides an excellent model for measuring rates of deletions of DNA sequences. Chloramphenicol resistant (Cm r ) reversion in this genetic selection system reports complete or partial deletion, as well as simple frameshift mutations [44,[48][49][50][51]. To ascertain potential differences in rates of instability when the G-rich strand comprises the leading or lagging strands of replication, the orientation of the unidirectional ColE1 replication origin and ampicillin gene was reversed creating pBR235-based plasmids.…”

Section: Measurement Of CM R or Tet R Mutation Rates And Analysis Of mentioning

confidence: 99%

Role of Hfq in Genome Evolution: Instability of G-Quadruplex Sequences in E. coli

et al. 2019

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Certain G-rich DNA repeats can form quadruplex in bacterial chromatin that can present blocks to DNA replication and, if not properly resolved, may lead to mutations. To understand the participation of quadruplex DNA in genomic instability in Escherichia coli (E. coli), mutation rates were measured for quadruplex-forming DNA repeats, including (G 3 T) 4 , (G 3 T) 8 , and a RET oncogene sequence, cloned as the template or nontemplate strand. We evidence that these alternative structures strongly influence mutagenesis rates. Precisely, our results suggest that G-quadruplexes form in E. coli cells, especially during transcription when the G-rich strand can be displaced by R-loop formation. Structure formation may then facilitate replication misalignment, presumably associated with replication fork blockage, promoting genomic instability. Furthermore, our results also evidence that the nucleoid-associated protein Hfq is involved in the genetic instability associated with these sequences. Hfq binds and stabilizes G-quadruplex structure in vitro and likely in cells. Collectively, our results thus implicate quadruplexes structures and Hfq nucleoid protein in the potential for genetic change that may drive evolution or alterations of bacterial gene expression. variable with strands arranged in a parallel, antiparallel, or mixed orientations associated with various glycosidic configurations of guanines [1,[3][4][5]. A single repeat motif can often form multiple structures depending on ionic conditions, as shown for repeats at human telomeres and oncogene promoters [4][5][6][7]. When G-quadruplex structures form in duplex DNA, the C-rich DNA strand complementary to G-quadruplex-forming sequences can form a four stranded i-motif at low pH [8], in which two tracts of cytosines form interdigitated C•C + base pairs [7,9,10] (Figure 1C).Microorganisms 2019, 7, x 2 of 16 quartets are stabilized by monovalent cations. The topology of quadruplex structures is highly variable with strands arranged in a parallel, antiparallel, or mixed orientations associated with various glycosidic configurations of guanines [1,[3][4][5]. A single repeat motif can often form multiple structures depending on ionic conditions, as shown for repeats at human telomeres and oncogene promoters [4][5][6][7]. When G-quadruplex structures form in duplex DNA, the C-rich DNA strand complementary to G-quadruplex-forming sequences can form a four stranded i-motif at low pH [8], in which two tracts of cytosines form interdigitated C•C + base pairs [7,9,10] (Figure 1C).

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Section: Measurement Of CM R or Tet R Mutation Rates And Analysis Of mentioning

confidence: 99%

Role of Hfq in Genome Evolution: Instability of G-Quadruplex Sequences in E. coli

et al. 2019

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“…In fact, CCTG expansion is by far the largest expansion observed (11), with alleles ranging in size from ∼75 to 11 000 repeats (9,12), whereas CTG expansion only involves 50–2000 repeats. Earlier biochemical studies have suggested CCTG repeats lack the capacity to adopt a defined base-paired hairpin structure, contrary to the complementary CAGG repeats (13,14).…”

Section: Introductionmentioning

confidence: 99%

“…Earlier biochemical studies have suggested CCTG repeats lack the capacity to adopt a defined base-paired hairpin structure, contrary to the complementary CAGG repeats (13,14). Nevertheless, recent gel mobility and genetic assays have shown that both CCTG and CAGG repeats can form slipped-strand structures (11,15). Yet, no detailed features of the hairpin or slipped-strand structures have been reported.…”

Section: Introductionmentioning

confidence: 99%

The origin of genetic instability in CCTG repeats

Lam¹,

Wu²,

Yang³

et al. 2011

Nucleic Acids Research

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CCTG tetranucleotide repeat expansion is associated with a hereditary neurological disease called myotonic dystrophy type 2 (DM2). The underlying reasons that lead to genetic instability and thus repeat expansion during DNA replication remains elusive. Here, we have shown CCTG repeats have a high propensity to form metastable hairpin and dumbbell structures using high-resolution nuclear magnetic resonance (NMR) spectroscopy. When the repeat length is equal to three, a hairpin with a two-residue CT loop is formed. In addition to the hairpin, a dumbbell structure with two CT-loops is formed when the repeat length is equal to four. Nuclear Overhauser effect (NOE) and chemical shift data reveal both the hairpin and dumbbell structures contain a flexible stem comprising a C-bulge and a T·T mismatch. With the aid of single-site mutation samples, NMR results show these peculiar structures undergo dynamic conformational exchange. In addition to the intrinsic flexibility in the stem region of these structures, the exchange process also serves as an origin of genetic instability that leads to repeat expansion during DNA replication. The structural features provide important drug target information for developing therapeutics to inhibit the expansion process and thus the onset of DM2.

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“…Unpaired structures and various sister strand exchange events have been postulated to explain the instability of the pure ATTCT repeat [19, 20]. However, these mechanisms are likely to introduce a greater perturbation of the overall repeat structure, and the remarkable consistency in the location and sequence of these interruption motifs argues against such a mechanism for instability.…”

Section: Discussionmentioning

confidence: 99%

Inheritance patterns of ATCCT repeat interruptions in spinocerebellar ataxia type 10 (SCA10) expansions

et al. 2017

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Spinocerebellar ataxia type 10 (SCA10), an autosomal dominant cerebellar ataxia disorder, is caused by a non-coding ATTCT microsatellite repeat expansion in the ataxin 10 gene. In a subset of SCA10 families, the 5’-end of the repeat expansion contains a complex sequence of penta- and heptanucleotide interruption motifs which is followed by a pure tract of tandem ATCCT repeats of unknown length at its 3’-end. Intriguingly, expansions that carry these interruption motifs correlate with an epileptic seizure phenotype and are unstable despite the theory that interruptions are expected to stabilize expanded repeats. To examine the apparent contradiction of unstable, interruption-positive SCA10 expansion alleles and to determine whether the instability originates outside of the interrupted region, we sequenced approximately 1 kb of the 5’-end of SCA10 expansions using the ATCCT-PCR product in individuals across multiple generations from four SCA10 families. We found that the greatest instability within this region occurred in paternal transmissions of the allele in stretches of pure ATTCT motifs while the intervening interrupted sequences were stable. Overall, the ATCCT interruption changes by only one to three repeat units and therefore cannot account for the instability across the length of the disease allele. We conclude that the AT-rich interruptions locally stabilize the SCA10 expansion at the 5’-end but do not completely abolish instability across the entire span of the expansion. In addition, analysis of the interruption alleles across these families support a parsimonious single origin of the mutation with a shared distant ancestor.

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Genetic instabilities of (CCTG)·(CAGG) and (ATTCT)·(AGAAT) disease‐associated repeats reveal multiple pathways for repeat deletion

Cited by 14 publications

References 75 publications

Role of Hfq in Genome Evolution: Instability of G-Quadruplex Sequences in E. coli

Role of Hfq in Genome Evolution: Instability of G-Quadruplex Sequences in E. coli

The origin of genetic instability in CCTG repeats

Inheritance patterns of ATCCT repeat interruptions in spinocerebellar ataxia type 10 (SCA10) expansions

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