Encoded errors: mutations and rearrangements mediated by misalignment at repetitive DNA sequences

Lovett, Susan T.

doi:10.1111/j.1365-2958.2004.04076.x

Cited by 244 publications

(231 citation statements)

References 79 publications

(112 reference statements)

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“…Events of the type proposed here have been described by others in a variety of organisms (Persky and Lovett 2008). After replication fork stalling, single strands of nascent DNA are released and contribute to chromosome rearrangement (Lovett 2004). Short (imperfect) palindromic sequences are frequent (Stern et al 1984;Bachellier et al 1999;Vasconcelos et al 2000) and can form ''snap-back'' structures in single-stranded DNA (see Figure 2).…”

Section: Resultsmentioning

confidence: 89%

“…This synthesis must open the template duplex and is likely to be prone to template switching, which has been observed in many situations, especially for the PolA repair polymerase (Ross et al 1979;Ahmed and Podemski 1998;Pinder et al 1998;Lovett 2004;Lee et al 2007). Strand extension after this template switch generates a branched structure that can be resolved either by chromosome replication or by repair of the three-way junction to yield a symmetrical inversion duplication (see nick indicated in Figure 2).…”

Section: Resultsmentioning

confidence: 99%

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The Tandem Inversion Duplication inSalmonella enterica: Selection Drives Unstable Precursors to Final Mutation Types

et al. 2010

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During growth under selection, mutant types appear that are rare in unselected populations. Stressinduced mechanisms may cause these structures or selection may favor a series of standard events that modify common preexisting structures. One such mutation is the short junction (SJ) duplication with long repeats separated by short sequence elements: AB*(CD)*(CD)*E (* ¼ a few bases). Another mutation type, described here, is the tandem inversion duplication (TID), where two copies of a parent sequence flank an inverse-order segment: AB(CD)(E9D9C9B9)(CD)E. Both duplication types can amplify by unequal exchanges between direct repeats (CD), and both are rare in unselected cultures but common after prolonged selection for amplification. The observed TID junctions are asymmetric (aTIDs) and may arise from a symmetrical precursor (sTID)-ABCDE(E9D9C9B9A9)ABCDE-when sequential deletions remove each palindromic junction. Alternatively, one deletion can remove both sTID junctions to generate an SJ duplication. It is proposed that sTID structures form frequently under all growth conditions, but are usually lost due to their instability and fitness cost. Selection for increased copy number helps retain the sTID and favors deletions that remodel junctions, improve fitness, and allow higher amplification. Growth improves with each step in formation of an SJ or aTID amplification, allowing selection to favor completion of the mutation process.

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Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

The Tandem Inversion Duplication inSalmonella enterica: Selection Drives Unstable Precursors to Final Mutation Types

et al. 2010

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“…Our data suggest that DNA damage response proteins help to maintain genome stability by coordinating proper HR-mediated repair of spontaneous DSBs, some of which are likely to occur as a consequence of unusual nucleic acid structures that form during DNA replication (Bacolla et al 2004;Lovett 2004). Defects in DNA damage response proteins such as ATM, ATR, BRCA1, BRCA2, MRE11, and NBS1 result in familial cancer syndromes and confer GCRs such as inversions, translocations, or large deletions suggestive of DSB repair defects (Venkitaraman 2002).…”

Section: Resultsmentioning

confidence: 99%

Mutator Phenotype ofCaenorhabditis elegansDNA Damage Checkpoint Mutants

Harris¹,

Lowden²,

Clejan

et al. 2006

Genetics

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DNA damage response proteins identify sites of DNA damage and signal to downstream effectors that orchestrate either apoptosis or arrest of the cell cycle and DNA repair. The C. elegans DNA damage response mutants mrt-2, hus-1, and clk-2(mn159) displayed 8-to 15-fold increases in the frequency of spontaneous mutation in their germlines. Many of these mutations were small-to medium-sized deletions, some of which had unusual sequences at their breakpoints such as purine-rich tracts or direct or inverted repeats. Although DNA-damage-induced apoptosis is abrogated in the mrt-2, hus-1, and clk-2 mutant backgrounds, lack of the apoptotic branch of the DNA damage response pathway in cep-1/p53, ced-3, and ced-4 mutants did not result in a Mutator phenotype. Thus, DNA damage checkpoint proteins suppress the frequency of mutation by ensuring that spontaneous DNA damage is accurately repaired in C. elegans germ cells. Although DNA damage response defects that predispose humans to cancer are known to result in large-scale chromosome aberrations, our results suggest that small-to medium-sized deletions may also play roles in the development of cancer.

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“…A total of 9 out of 19 mutations are frameshift: seven are small insertions or deletions (o5 bp), one is a deletion of 12 bp (c.1127_1131del), and one is a duplication of 12 bp (c.1166_1178dup) (Table 1). Generally, frameshift muta- tions occur in stretches of repetitive DNA nucleotide runs that probably cause slippage errors of the DNA polymerase, at the replication fork [Lovett, 2004;Schmidt et al, 2005]. IKBKG exon 10 is particularly rich in mononucleotide tracts of cytosines (Fig.…”

Section: Ikbkg Mutational Hotspot In ''C N '' Runsmentioning

confidence: 99%

Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations

et al. 2008

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Communicated by Andrew O.M. WilkieMutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), also called nuclear factor-kappaB (NF-kB) essential modulator (NEMO), gene are the most common single cause of incontinentia pigmenti (IP) in females and anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males. The IKBKG gene, located in the Xq28 chromosomal region, encodes for the regulatory subunit of the inhibitor of kappaB (IkB) kinase (IKK) complex required for the activation of the NF-kB pathway. Therefore, the remarkably heterogeneous and often severe clinical presentation reported in IP is due to the pleiotropic role of this signaling transcription pathway. A recurrent exon 4_10 genomic rearrangement in the IKBKG gene accounts for 60 to 80% of IP-causing mutations. Besides the IKBKG rearrangement found in IP females (which is lethal in males), a total of 69 different small mutations (missense, frameshift, nonsense, and splice-site mutations) have been reported, including 13 novel ones in this work. The updated distribution of all the IP-and EDA-ID-causing mutations along the IKBKG gene highlights a secondary hotspot mutation in exon 10, which contains only 11% of the protein. Furthermore, familial inheritance analysis revealed an unexpectedly high incidence of sporadic cases (465%). The sum of the observations can aid both in determining the molecular basis of IP and EDA-ID allelic diseases, and in genetic counseling in affected families. Hum Mutat 29(5), [595][596][597][598][599][600][601][602][603][604] 2008.

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Encoded errors: mutations and rearrangements mediated by misalignment at repetitive DNA sequences

Cited by 244 publications

References 79 publications

The Tandem Inversion Duplication inSalmonella enterica: Selection Drives Unstable Precursors to Final Mutation Types

The Tandem Inversion Duplication inSalmonella enterica: Selection Drives Unstable Precursors to Final Mutation Types

Mutator Phenotype ofCaenorhabditis elegansDNA Damage Checkpoint Mutants

Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations

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