Conditional mutation of <i>Smc5</i> in mouse embryonic stem cells perturbs condensin localization and mitotic progression

Pryzhkova, Marina V.; Jordan, Philip W.

doi:10.1242/jcs.179036

Cited by 23 publications

(54 citation statements)

References 71 publications

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“…In the case of SMC6 , however, we were unable to generate any CRISPR-modified cells. Previous papers show that ablation of SMC6 resulted in embryonic lethality in mice [26] and that conditional knockout of SMC5 in mouse embryonic stem cells induced apoptosis [28]. Therefore, the failure to generate SMC6 -deprived clones in our studies most likely reflects that SMC6 is also essential for cell survival in humans.…”

Section: Discussionmentioning

confidence: 69%

“…NSMCE2 has also been shown to be essential for mouse development and it can suppress cancer and aging by limiting recombination and facilitating chromosome segregation [27]. In line with these studies, a recent paper describes that depletion of SMC5 in mouse embryonic stem cells led to accumulation of cells in G2 and subsequent mitotic failure and apoptosis [28]. …”

Section: Introductionmentioning

confidence: 99%

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

Verver

Zheng

Speijer

et al. 2016

IJMS

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The structural maintenance of chromosomes (SMC) protein complexes shape and regulate the structure and dynamics of chromatin, thereby controlling many chromosome-based processes such as cell cycle progression, differentiation, gene transcription and DNA repair. The SMC5/6 complex is previously described to promote DNA double-strand breaks (DSBs) repair by sister chromatid recombination, and found to be essential for resolving recombination intermediates during meiotic recombination. Moreover, in budding yeast, SMC5/6 provides structural organization and topological stress relief during replication in mitotically dividing cells. Despite the essential nature of the SMC5/6 complex, the versatile mechanisms by which SMC5/6 functions and its molecular regulation in mammalian cells remain poorly understood. By using a human osteosarcoma cell line (U2OS), we show that after the CRISPR-Cas9-mediated removal of the SMC5/6 subunit NSMCE2, treatment with the topoisomerase II inhibitor etoposide triggered an increased sensitivity in cells lacking NSMCE2. In contrast, NSMCE2 appeared not essential for a proper DNA damage response or cell survival after DSB induction by ionizing irradiation (IR). Interestingly, by way of immunoprecipitations (IPs) and mass spectrometry, we found that the SMC5/6 complex physically interacts with the DNA topoisomerase II α (TOP2A). We therefore propose that the SMC5/6 complex functions in resolving TOP2A-mediated DSB-repair intermediates generated during replication.

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

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

Verver

Zheng

Speijer

et al. 2016

IJMS

View full text Add to dashboard Cite

show abstract

“…Since Nestin is expressed in progenitor cells of tissues other than neural, some degree of DNA excision was also observed in kidneys and muscles in our samples ( Figure 1B and Figure 1-figure supplement 1A) (Bernal et al, 2018;Sakairi et al, 2007). SMC5 depletion in the developing mouse cortex resulted in a significant increase in cleaved caspase 3 (CASP3)-positive cells in Smc5 cKO compared to controls in both, E13.5 and E16.5 cortices ( Figure We have previously shown that the depletion of SMC5 in mESCs causes chromosome segregation defects during mitosis (Hwang et al, 2017;Pryzhkova and Jordan, 2016). Thus, we analyzed VZ and SVZ mitotic progenitors in cortical sections of E13.5 and E16.…”

Section: Smc5 Cko Causes Neurodevelopmental and Sensorimotor Defects mentioning

confidence: 97%

SMC5/6 is required for replication fork stability and faithful chromosome segregation during neurogenesis

Atkins

et al. 2020

eLife

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Mutations of SMC5/6 components cause developmental defects, including primary microcephaly. To model neurodevelopmental defects, we engineered a mouse wherein Smc5 is conditionally knocked out (cKO) in the developing neocortex. Smc5 cKO mice exhibited neurodevelopmental defects due to neural progenitor cell (NPC) apoptosis, which led to reduction in cortical layer neurons. Smc5 cKO NPCs formed DNA bridges during mitosis and underwent chromosome missegregation. SMC5/6 depletion triggers a CHEK2-p53 DNA damage response, as concomitant deletion of the Trp53 tumor suppressor or Chek2 DNA damage checkpoint kinase rescued Smc5 cKO neurodevelopmental defects. Further assessment using Smc5 cKO and auxin-inducible degron systems demonstrated that absence of SMC5/6 leads to DNA replication stress at late-replicating regions such as pericentromeric heterochromatin regions. In summary, SMC5/6 is important for completion of DNA replication prior to entering mitosis, which ensures accurate chromosome segregation. Thus, SMC5/6 functions are critical in highly proliferative stem cells during organism development.

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“…Although the function of this complex is mostly outside of mitosis, its impact on chromosome organization also influences mitotic chromosome morphology. Direct evidence for the importance of SMC5/6 to mitotic chromosome assembly is based on observations that human cells lacking SMC6 or SMC5 display defective chromosome morphology and faulty mitotic localization of topoisomerase II or condensin [ 112 , 113 ]. Whether or not the SMC5/6 complex is present on mitotic chromatin has been controversial.…”

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

confidence: 99%

“…Whether or not the SMC5/6 complex is present on mitotic chromatin has been controversial. Whereas some studies reveal it is virtually absent from mitotic chromosomes [ 112 ], others report an enrichment at pericentromeric regions, at the chromosomal axis, and at DNA bridges caused by topoisomerase II inhibition [ 113 , 114 ]. It thus remains unclear if this complex is actively shaping chromatin during mitosis.…”

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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Conditional mutation of Smc5 in mouse embryonic stem cells perturbs condensin localization and mitotic progression

Cited by 23 publications

References 71 publications

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

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

SMC5/6 is required for replication fork stability and faithful chromosome segregation during neurogenesis

A Topology-Centric View on Mitotic Chromosome Architecture

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