Impact of mismatch repair deficiency on genomic stability in the maternal germline and during early embryonic development

Larson, Jon S.; Stringer, Saundra L.; Stringer, James R.

doi:10.1016/j.mrfmmm.2004.06.036

Cited by 10 publications

(8 citation statements)

References 31 publications

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“…The embryonic lethality of these mutants impedes investigation into the maternal function of DDR genes. Until now, only maternal PMS2 ( postmeiotic segregation increased 2), a mammalian homologue of a bacterial DNA mismatch repair protein, is reported to play a role in DDR in mouse development (Larson et al, 2004). Embryos lacking maternal UBE2A (ubiquitinconjugating enzyme E2A), a homologue of the ubiquitinconjugating enzyme RAD6 involved in DNA repair in yeast, arrest development at the two-cell stage.…”

Section: Introductionmentioning

confidence: 99%

Maternal BCAS2 protects genomic integrity in mouse early embryonic development

Wang

Xiang

et al. 2015

Development

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Mammalian early embryos maintain accurate genome integrity for proper development within a programmed timeline despite constant assaults on their DNA by replication, DNA demethylation and genetic defects transmitted from germ cells. However, how genome integrity is safeguarded during mammalian early embryonic development remains unclear. BCAS2 (breast carcinoma amplified sequence 2), a core component of the PRP19 complex involved in pre-mRNA splicing, plays an important role in the DNA damage response through the RPA complex, a key regulator in the maintenance of genome integrity. Currently, the physiological role of BCAS2 in mammals is unknown. We now report that BCAS2 responds to endogenous and exogenous DNA damage in mouse zygotes. Maternal depletion of BCAS2 compromises the DNA damage response in early embryos, leading to developmental arrest at the two-to four-cell stage accompanied by the accumulation of damaged DNA and micronuclei. Furthermore, BCAS2 mutants that are unable to bind RPA1 fail in DNA repair during the zygotic stage. In addition, phosphorylated RPA2 cannot localise to the DNA damage sites in mouse zygotes with disrupted maternal BCAS2. These data suggest that BCAS2 might function through the RPA complex during DNA repair in zygotes. Together, our results reveal that maternal BCAS2 maintains the genome integrity of early embryos and is essential for female mouse fertility.

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Section: Introductionmentioning

confidence: 99%

Maternal BCAS2 protects genomic integrity in mouse early embryonic development

Wang

Xiang

et al. 2015

Development

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“…However, based on the presented model, we argue that the high repeat content in MMR regions may be explained by less than 100-fold difference in microsatellite mutation rate between the MMR wild-type and the heterozygous mutant. This level of instability is in the lower range of that observed in MMR deficient tumors (Lynch et al 2006; Sammalkorpi et al 2007) and in the germline of MMR deficient and insufficient mice (Larson et al 2004; Gurtu et al 2002). …”

Section: Discussionmentioning

confidence: 89%

“…Still, evidence from animal studies and cell lines, show that even heterozygous MMR mutations may produce an increase in mutation rate (Zhang et al 2002; Alazzouzi et al 2005; Bouffler et al 2000), and such haploinsufficiency has also been detected in the germline (Larson et al 2004; Gurtu et al 2002; Baida et al 2003). …”

Section: Introductionmentioning

confidence: 99%

Unstable DNA Repair Genes Shaped by Their Own Sequence Modifying Phenotypes

et al. 2010

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The question of whether natural selection favors genetic stability or genetic variability is a fundamental problem in evolutionary biology. Bioinformatic analyses demonstrate that selection favors genetic stability by avoiding unstable nucleotide sequences in protein encoding DNA. Yet, such unstable sequences are maintained in several DNA repair genes, thereby promoting breakdown of repair and destabilizing the genome. Several studies have therefore argued that selection favors genetic variability at the expense of stability. Here we propose a new evolutionary mechanism, with supporting bioinformatic evidence, that resolves this paradox. Combining the concepts of gene-dependent mutation biases and meiotic recombination, we argue that unstable sequences in the DNA mismatch repair (MMR) genes are maintained by their own phenotype. In particular, we predict that human MMR maintains an overrepresentation of mononucleotide repeats (monorepeats) within and around the MMR genes. In support of this hypothesis, we report a 31% excess in monorepeats in 250 kb regions surrounding the seven MMR genes compared to all other RefSeq genes (1.75 vs. 1.34%, P = 0.0047), with a particularly high content in PMS2 (2.41%, P = 0.0047) and MSH6 (2.07%, P = 0.043). Based on a mathematical model of monorepeat frequency, we argue that the proposed mechanism may suffice to explain the observed excess of repeats around MMR genes. Our findings thus indicate that unstable sequences in MMR genes are maintained through evolution by the MMR mechanism. The evolutionary paradox of genetically unstable DNA repair genes may thus be explained by an equilibrium in which the phenotype acts back on its own genotype.Electronic supplementary materialThe online version of this article (doi:10.1007/s00239-010-9328-0) contains supplementary material, which is available to authorized users.

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“…The G11 PLAP mouse model offers the advantage of making it possible to see the mutant cells within a tissue, thereby revealing the types of cells that incur mutations (DePrimo et al ., 1996Cao et al ., 1998;Hersh et al ., 2002;Larson et al ., 2004;Stringer et al ., 2004Stringer et al ., , 2005Fischer et al ., 2005). G11 PLAP mice carry a mutant allele (G11) of a human Placental Alkaline Phosphatase (PLAP) transgene.…”

Section: Introductionmentioning

confidence: 99%

“…By contrast, there was no evidence that mistakes made during transcription or translation contributed to production of PLAP activity . Lack of mismatch repair increased the frequency of cells expressing PLAP activity by more than 100-fold (Hersh et al ., 2002;Larson et al ., 2004). Similar results were obtained in experiments in mice that carry a mononucleotide repeat in a transgene encoding the sitespecific recombinase, cre (Akyol et al ., 2008;Miller et al ., 2008).…”

Section: Introductionmentioning

confidence: 99%

Mutation in aging mice occurs in diverse cell types that proliferate postmutation

Fischer

Stringer

2008

Aging Cell

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SummaryTo determine the relationship between aging, cell proliferation and mutation in different cell types, hearts, brains and kidneys from G11 PLAP mice between 1 week and 24 months of age were examined. Mutant cells were Regardless of tissue and cell type, PLAP + cells occurred as singletons and in clusters, both of which increased in frequency with age. These data show that age-associated accumulation of mutant cells occurs in diverse cell types and is due to both new mutation and proliferation of mutant cells, even in cell types that tend to not proliferate.

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Impact of mismatch repair deficiency on genomic stability in the maternal germline and during early embryonic development

Cited by 10 publications

References 31 publications

Maternal BCAS2 protects genomic integrity in mouse early embryonic development

Maternal BCAS2 protects genomic integrity in mouse early embryonic development

Unstable DNA Repair Genes Shaped by Their Own Sequence Modifying Phenotypes

Mutation in aging mice occurs in diverse cell types that proliferate postmutation

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