Maternal <i>Smc3</i> protects the integrity of the zygotic genome through DNA replication and mitosis

Yueh, Wei-Ting; Singh, Vijay Pratap; Gerton, Jennifer L.

doi:10.1242/dev.199800

Cited by 10 publications

(11 citation statements)

References 94 publications

(138 reference statements)

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“…Thus, we sought to further characterize LoF constraint in SMC3. Consistent with in vitro 38,39 and model organism studies 9,10,40,41 indicating SMC3 is an essential developmental gene, biallelic pLoF variants have never been described in a human being, including our cases.…”

Section: Smc3 Mutational Constraintsupporting

confidence: 90%

“…In mice, sufficient SMC3 protein is required in oocytes for early embryonic development, 10 and heterozygous depletion of SMC3 in female mice has deleterious impacts on both the integrity and transmission of zygotic chromosomes. 9,10,12 Furthermore, conditional knockout of HDAC8 , an SMC3 recycling factor, causes subfertility. 57 Finally, several cohesin or cohesin-related genes have been implicated in infertility in humans ( REC8 , SMC1B , STAG3 , SGO2 ).…”

Section: Discussionmentioning

confidence: 99%

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Heterozygous loss-of-functionSMC3variants are associated with variable and incompletely penetrant growth and developmental features

Ansari,

Faour,

Shimamura

et al. 2023

Preprint

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Heterozygous missense variants and in-frame indels inSMC3are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, and dysmorphism, via an apparent dominant-negative mechanism. However, the spectrum of manifestations associated withSMC3loss-of-function variants has not been reported, leading to hypotheses of alternative phenotypes or even developmental lethality. We used matchmaking servers, patient registries, and other resources to identify individuals with heterozygous, predicted loss-of-function (pLoF) variants inSMC3, and analyzed population databases to characterize mutational intolerance in this gene. Here, we show thatSMC3behaves as an archetypal haploinsufficient gene: it is highly constrained against pLoF variants, strongly depleted for missense variants, and pLoF variants are associated with a range of developmental phenotypes. Among 13 individuals withSMC3pLoF variants, phenotypes were variable but coalesced on low growth parameters, developmental delay/intellectual disability, and dysmorphism reminiscent of atypical CdLS. Comparisons to individuals withSMC3missense/in-frame indel variants demonstrated a milder presentation in pLoF carriers. Furthermore, several individuals harboring pLoF variants inSMC3were nonpenetrant for growth, developmental, and/or dysmorphic features, some instead having intriguing symptomatologies with rational biological links toSMC3including bone marrow failure, acute myeloid leukemia, and Coats retinal vasculopathy. Analyses of transcriptomic and epigenetic data suggest thatSMC3pLoF variants reduceSMC3expression but do not result in a blood DNA methylation signature clustering with that of CdLS, and that the global transcriptional signature ofSMC3loss is model-dependent. Our finding of substantial population-scale LoF intolerance in concert with variable penetrance in subjects withSMC3pLoF variants expands the scope of cohesinopathies, informs on their allelic architecture, and suggests the existence of additional clearly LoF-constrained genes whose disease links will be confirmed only by multi-layered genomic data paired with careful phenotyping.

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Section: Smc3 Mutational Constraintsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Heterozygous loss-of-functionSMC3variants are associated with variable and incompletely penetrant growth and developmental features

Ansari,

Faour,

Shimamura

et al. 2023

Preprint

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“…Similar to C. elegans spo-11 rec-8 mutants, Drosophila sunn mutants lack SCC but retain non-cohesive c(2)m/SA cohesin (at least in pachytene) and form bipolar metaphase I spindles (Gyuricza et al, 2016). Depletion of SMC3, which should remove all cohesin from chromatin, has been reported in mouse oocytes (Yueh, Singh, & Gerton, 2021) and Drosophila oocytes (Gyuricza et al, 2016). Metaphase I spindle defects were not reported in either case.…”

Section: Discussionmentioning

confidence: 98%

Cohesin is required for meiotic spindle assembly independent of its role in cohesion in C. elegans

McNally

Danlasky

Barroso

et al. 2022

Preprint

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Accurate chromosome segregation requires a cohesin-mediated physical attachment between chromosomes that are to be segregated apart, and a bipolar spindle with microtubule plus ends emanating from exactly two poles toward the paired chromosomes. We asked whether the striking bipolar structure of C. elegans meiotic chromosomes is required for bipolarity of acentriolar female meiotic spindles by analyzing mutants that lack cohesion between chromosomes. Both a spo-11, rec-8, coh-3, coh-4 quadruple mutant and a spo-11, rec-8 double mutant entered M phase with single chromatids lacking any cohesion. However, the quadruple mutant formed an apolar spindle whereas the double mutant formed a bipolar spindle that segregated chromatids into two roughly equal masses. Residual non-cohesive COH -3/4-dependent cohesin on single chromatids of the double mutant was sufficient to recruit haspin-dependent Aurora B kinase, which regulated the localization of the spindle-assembly factors CLASP-2 and kinesin-13 to mediate bipolar spindle assembly in the apparent absence of chromosomal bipolarity. These results demonstrate that cohesin is essential for spindle assembly and chromosome segregation independent of its role in sister chromatid cohesion.

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“…Depletion of SMC3, which should remove all cohesin from chromatin, has been reported in mouse oocytes [ 67 ] and Drosophila oocytes [ 68 ]. Metaphase I spindle defects were not reported in either case.…”

Section: Discussionmentioning

confidence: 99%

Cohesin is required for meiotic spindle assembly independent of its role in cohesion in C. elegans

McNally

Beath²,

Danlasky³

et al. 2022

PLoS Genet

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Accurate chromosome segregation requires a cohesin-mediated physical attachment between chromosomes that are to be segregated apart, and a bipolar spindle with microtubule plus ends emanating from exactly two poles toward the paired chromosomes. We asked whether the striking bipolar structure of C. elegans meiotic chromosomes is required for bipolarity of acentriolar female meiotic spindles by time-lapse imaging of mutants that lack cohesion between chromosomes. Both a spo-11 rec-8 coh-4 coh-3 quadruple mutant and a spo-11 rec-8 double mutant entered M phase with separated sister chromatids lacking any cohesion. However, the quadruple mutant formed an apolar spindle whereas the double mutant formed a bipolar spindle that segregated chromatids into two roughly equal masses. Residual non-cohesive COH-3/4-dependent cohesin on separated sister chromatids of the double mutant was sufficient to recruit haspin-dependent Aurora B kinase, which mediated bipolar spindle assembly in the apparent absence of chromosomal bipolarity. We hypothesized that cohesin-dependent Aurora B might activate or inhibit spindle assembly factors in a manner that would affect their localization on chromosomes and found that the chromosomal localization patterns of KLP-7 and CLS-2 correlated with Aurora B loading on chromosomes. These results demonstrate that cohesin is essential for spindle assembly and chromosome segregation independent of its role in sister chromatid cohesion.

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Maternal Smc3 protects the integrity of the zygotic genome through DNA replication and mitosis

Cited by 10 publications

References 94 publications

Heterozygous loss-of-functionSMC3variants are associated with variable and incompletely penetrant growth and developmental features

Heterozygous loss-of-functionSMC3variants are associated with variable and incompletely penetrant growth and developmental features

Cohesin is required for meiotic spindle assembly independent of its role in cohesion in C. elegans

Cohesin is required for meiotic spindle assembly independent of its role in cohesion in C. elegans

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