Non-SMC Element 2 (NSMCE2) of the SMC5/6 Complex Helps to Resolve Topological Stress

Verver, Dideke E.; Zheng, Yi; Speijer, Dave; Hoebe, Ron A.; Dekker, Henk; Repping, Sjoerd; Stap, Jan; Hamer, Geert

doi:10.3390/ijms17111782

Cited by 26 publications

(29 citation statements)

References 66 publications

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“…Previous reports have shown that mutation of SMC5/6 components causes sensitivity to etoposide, and SMC5/6 colocalizes and interacts with topoisomerase IIα (Gómez et al , 2013; Verver et al , 2016b). To determine whether the Smc5 mutant germ cells were also susceptible to etoposide, adult Smc5 flox/del , Stra8-Cre cKO and control mice were injected with etoposide and assessed for defects 3, 5, and 8 d postinjection (Figure 8).…”

Section: Resultsmentioning

confidence: 99%

“…Results of small interfering RNA (siRNA)-mediated knockdown and mutation studies using human cell lines reveal that depletion of the SMC5/6 complex leads to increased genome instability when exposed to exogenous DNA damage, including irradiation and etoposide exposures (Wu et al , 2012; Payne et al , 2014; Verver et al , 2016b). Therefore, we assessed whether Smc5 cKO prophase spermatocytes had elevated abnormalities when exposed to gamma irradiation and etoposide.…”

Section: Resultsmentioning

confidence: 99%

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Depletion of SMC5/6 sensitizes male germ cells to DNA damage

Hwang

Verver

Handel

et al. 2018

MBoC

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The structural maintenance of chromosomes complex SMC5/6 is thought to be essential for DNA repair and chromosome segregation during mitosis and meiosis. To determine the requirements of the SMC5/6 complex during mouse spermatogenesis we combined a conditional knockout allele for Smc5, with four germ cell–specific Cre-recombinase transgenes, Ddx4-Cre, Stra8-Cre, Spo11-Cre, and Hspa2-Cre, to mutate Smc5 in spermatogonia, in spermatocytes before meiotic entry, during early meiotic stages, and during midmeiotic stages, respectively. Conditional mutation of Smc5 resulted in destabilization of the SMC5/6 complex. Despite this, we observed only mild defects in spermatogenesis. Mutation of Smc5 mediated by Ddx4-Cre and Stra8-Cre resulted in partial loss of preleptotene spermatocytes; however, spermatogenesis progresses and mice are fertile. Mutation of Smc5 via Spo11-Cre or Hspa2-Cre did not result in detectable defects of spermatogenesis. Upon exposure to gamma irradiation or etoposide treatment, each conditional Smc5 mutant demonstrated an increase in the number of enlarged round spermatids with multiple acrosomes and supernumerary chromosome content. We propose that the SMC5/6 complex is not acutely required for premeiotic DNA replication and meiotic progression during mouse spermatogenesis; however, when germ cells are challenged by exogenous DNA damage, the SMC5/6 complex ensures genome integrity, and thus, fertility.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Depletion of SMC5/6 sensitizes male germ cells to DNA damage

Hwang

Verver

Handel

et al. 2018

MBoC

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“…Yeast SMC5/6 was observed to accumulate at sister chromatid intertwine sites, and topoisomerase II was needed for the resolution of those links [ 109 , 110 ]. Similarly, human topoisomerase II was shown to physically interact with SMC5/6 subunits, in order to resolve topological entanglements during replication [ 111 ]. Although the function of this complex is mostly outside of mitosis, its impact on chromosome organization also influences mitotic chromosome morphology.…”

Section: Regulation Of Topoisomerase II Activity: Guidance By the mentioning

confidence: 99%

A Topology-Centric View on Mitotic Chromosome Architecture

Piskadlo

Oliveira

2017

IJMS

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Mitotic chromosomes are long-known structures, but their internal organization and the exact process by which they are assembled are still a great mystery in biology. Topoisomerase II is crucial for various aspects of mitotic chromosome organization. The unique ability of this enzyme to untangle topologically intertwined DNA molecules (catenations) is of utmost importance for the resolution of sister chromatid intertwines. Although still controversial, topoisomerase II has also been proposed to directly contribute to chromosome compaction, possibly by promoting chromosome self-entanglements. These two functions raise a strong directionality issue towards topoisomerase II reactions that are able to disentangle sister DNA molecules (in trans) while compacting the same DNA molecule (in cis). Here, we review the current knowledge on topoisomerase II role specifically during mitosis, and the mechanisms that directly or indirectly regulate its activity to ensure faithful chromosome segregation. In particular, we discuss how the activity or directionality of this enzyme could be regulated by the SMC (structural maintenance of chromosomes) complexes, predominantly cohesin and condensin, throughout mitosis.

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“…However, we could envisage a possible prognostic implication given that Group A comprised three out the five cases with complex karyotype and TP53 mutation/17p13 loss, which are notoriously associated with a poorer outcome in AML [ 3 ]. Interestingly, NSMCE2 , which was overexpressed in Group A cases, is required for DNA double-strand break repair and genomic integrity maintenance [ 41 , 42 ]. Its depletion was shown to sensitize HeLa cells to DNA damage-induced apoptosis [ 43 ] suggesting that, alternatively, its overexpression could make tumor cells more resistant to the DNA damage induced by their wide genomic rearrangements.…”

Section: Discussionmentioning

confidence: 99%

MYC-containing amplicons in acute myeloid leukemia: genomic structures, evolution, and transcriptional consequences

et al. 2018

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Double minutes (dmin), homogeneously staining regions, and ring chromosomes are vehicles of gene amplification in cancer. The underlying mechanism leading to their formation as well as their structure and function in acute myeloid leukemia (AML) remain mysterious. We combined a range of high-resolution genomic methods to investigate the architecture and expression pattern of amplicons involving chromosome band 8q24 in 23 cases of AML (AML-amp). This revealed that different MYC-dmin architectures can coexist within the same leukemic cell population, indicating a step-wise evolution rather than a single event origin, such as through chromothripsis. This was supported also by the analysis of the chromothripsis criteria, that poorly matched the model in our samples. Furthermore, we found that dmin could evolve toward ring chromosomes stabilized by neocentromeres. Surprisingly, amplified genes (mainly PVT1) frequently participated in fusion transcripts lacking a corresponding DNA template. We also detected a significant overexpression of the circular RNA of PVT1 (circPVT1) in AML-amp cases versus AML with a normal karyotype. Our results show that 8q24 amplicons in AML are surprisingly plastic DNA structures with an unexpected association to novel fusion transcripts and circular RNAs.

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Non-SMC Element 2 (NSMCE2) of the SMC5/6 Complex Helps to Resolve Topological Stress

Cited by 26 publications

References 66 publications

Depletion of SMC5/6 sensitizes male germ cells to DNA damage

Depletion of SMC5/6 sensitizes male germ cells to DNA damage

A Topology-Centric View on Mitotic Chromosome Architecture

MYC-containing amplicons in acute myeloid leukemia: genomic structures, evolution, and transcriptional consequences

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