Trinucleotide expansion in haploid germ cells by gap repair

Kovtun, Irina V.; McMurray, Cynthia T.

doi:10.1038/86906

Cited by 261 publications

(215 citation statements)

References 28 publications

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“…The data showing the lack of measurable effects of meiotic events on the frequency of ESTR mutation in the male germline is consistent with the results of our previous study which failed to detect any correlation between meiotic crossing over and ESTR mutation induction [18]. Using a similar approach for cell sorting and a small-pool PCR technique, the frequency of microsatellite mutation was studied in transgenic mice carrying expanded disease-causing human microsatellite [19]. The results of this study showed that microsatellite expansion almost exclusively occurs in haploid spermatids and thus may be attributed to the repair of DNA gaps within repeats inappropriately folded into secondary structures.…”

supporting

confidence: 90%

Stage-specificity of spontaneous mutation at a tandem repeat DNA locus in the mouse germline

Shanks¹,

Riou²,

Fouchet³

et al. 2008

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Mouse expanded simple tandem repeat (ESTR) loci are the most unstable loci in the mouse genome. Despite the fact that over the last decade these loci have been extensively used for studying germline mutation induction in mice, to date little is known about the mechanisms underlying spontaneous and induced ESTR mutation. Here we used flow cytometry and single-molecule PCR to compare the frequency of ESTR mutation in four flow-sorted fractions of the mouse male germ cells -spermatogonia, spermatocytes I, round and elongated spermatids. The frequency and the spectrum of ESTR mutation did not significantly differ between different stages of mouse spermatogenesis. Considering these data and the results of other publications, we propose that spontaneous ESTR mutation is mostly attributed to replication slippage in spermatogonia and these loci may be regarded as a class of expanded microsatellites. IntroductionThe results of some recent publication show that mouse ESTR loci provide a sensitive technique for studying germline mutation induction following exposure to ionising radiation and chemical mutagens [1,2]. ESTR loci consist of long homogenous arrays of relatively short repeats (4-9 bp) and show a very high spontaneous mutation rate of length changes both in germline and somatic cells [3][4][5]. In this respect they clearly differ from another group of highly unstable tandem repeat DNA loci -the GC-rich human minisatellites, where the bulk of spontaneous mutations occur in the germline with very rare events taking place in the somatic cells [6]. Given this, ESTRs more closely resemble some microsatellite loci showing equally high instability in the germline and somatic tissues. In many publications it has been suggested, though not experimentally proven, that microsatellite mutation is most probably attributed to replication slippage [7]. However, numerous studies have also identified a unique class of the expanded disease-causing human microsatellites i.e., trinucleotide instability, which is clearly attributed to non-replication mechanisms [8]. It therefore remains unclear whether the very high spontaneous instability at ESTR loci is replication-driven or may be attributed to some other mechanisms. Here, to elucidate the still unknown mechanisms of ESTR spontaneous mutation, we have compared ESTR mutation frequencies in flow-sorted fractions of the male germ cells. Materials and methods Flow cytometryCBA/J male mice (Iffa Credo, Charles River, France) were used in this study. Cells were isolated from 3 month-old male mice using a two-step enzymatic digestion as previously described [9]. Magnetic-activated cell sorting (MACS) of α 6 -integrin positive cells was performed as we previously described [9] using rat anti-α 6 -integrin antibodies (GoH3, BD Biosciences) and mouse anti-rat Kappa antibody coupled to magnetic microbeads (Miltenyi Biotec, Paris, France). Testicular cell suspension, MACS α 6 -integrin-positive and negative cellular fractions were collected and suspended at 10 6 cells/ml for DNA stain...

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supporting

confidence: 90%

Stage-specificity of spontaneous mutation at a tandem repeat DNA locus in the mouse germline

Shanks¹,

Riou²,

Fouchet³

et al. 2008

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…MSH2-MSH3 also plays an important role in trinucleotide repeat expansion, the process that underlies several hereditary and progressive neurodegenerative diseases such as Huntington disease, myotonic dystrophy, and fragile-X syndrome (Cummings and Zoghbi, 2000). In the mouse, somatic and germline expansions of the CAG-CTG repeat within the Huntington's gene requires MSH2 (Kovtun and McMurray, 2001;Manley et al, 1999;Wheeler et al, 2003). Repeat instability is reduced in MSH3-null mice but elevated in MSH6-null mice pointing to a role for MSH3 in promoting repeat instability (van den Broek et al, 2002).…”

Section: Other Functions Of Mmrmentioning

confidence: 99%

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Hsieh

Yamane

2008

Mechanisms of Ageing and Development

397

359

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DNA mismatch repair (MMR) proteins are ubiquitous players in a diverse array of important cellular functions. In its role in post-replication repair, MMR safeguards the genome correcting base mispairs arising as a result of replication errors. Loss of MMR results in greatly increased rates of spontaneous mutation in organisms ranging from bacteria to humans. Mutations in MMR genes cause hereditary nonpolyposis colorectal cancer, and loss of MMR is associated with a significant fraction of sporadic cancers. Given its prominence in mutation avoidance and its ability to target a range of DNA lesions, MMR has been under investigation in studies of ageing mechanisms. This review summarizes what is known about the molecular details of the MMR pathway and the role of MMR proteins in cancer susceptibility and ageing.

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“…Using a Huntington disease mouse model, carrying a high number of CAG repeats, McMurray and Kovtun demonstrated that the repeat expansion was occurring between round spermatids and spermatozoa [McMurray and Kortun 2003]. Interestingly, the deletion of MSH2 in this mice model abolished the expansion [Kovtun and McMurray 2001], suggesting that MSH2 is active when extensive DNA repair occurs. Additional efforts are needed to identify the proteins involved in the repair process of ES.…”

Section: Further Evidence Of a Dna Repair System In Spermatidsmentioning

confidence: 99%

Spermiogenesis and DNA Repair: A Possible Etiology of Human Infertility and Genetic Disorders

Leduc¹,

Nkoma²,

Boissonneault³

2008

Systems Biology in Reproductive Medicine

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This paper reviews the possible origin of sperm DNA fragmentation and focuses on the nuclear events associated with spermiogenesis as a potential source of genetic instability and reduced fertilizing potential of the mature male gamete. Recent findings suggest a programmed DNA fragmentation and DNA damage response during the chromatin remodeling steps in spermatids. We also discuss the spermatid DNA repair mechanisms and the possible involvement of condensing proteins, such as transition proteins and protamines, in the process, as this DNA fragmentation is normally not found in late spermatids. We propose that alterations in the chromatin remodeling steps or DNA repair in elongating spermatids may lead to persistent DNA breaks. This vulnerable step of spermiogenesis may provide a clue to the etiology of sperm DNA fragmentation associated with infertility in humans. This vulnerability is further emphasized given the haploid character of spermatids that must resolve programmed double-stranded breaks by an error-prone DNA repair mechanism. Therefore, spermiogenesis has probably been overlooked as an important source of genetic instability.

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Trinucleotide expansion in haploid germ cells by gap repair

Cited by 261 publications

References 28 publications

Stage-specificity of spontaneous mutation at a tandem repeat DNA locus in the mouse germline

Stage-specificity of spontaneous mutation at a tandem repeat DNA locus in the mouse germline

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Spermiogenesis and DNA Repair: A Possible Etiology of Human Infertility and Genetic Disorders

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