Deficiency in SNM1 Abolishes an Early Mitotic Checkpoint Induced by Spindle Stress

Akhter, Shamima; Richie, Christopher T.; Deng, Jian Min; Brey, Eric M.; Zhang, Xiaoshan; Patrick, C.; Behringer, Richard R.; Legerski, Randy J.

doi:10.1128/mcb.24.23.10448-10455.2004

Cited by 30 publications

(38 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…How any putative kinetochore or checkpoint defects in 53BP1 mutants contribute to T cell lymphomagenesis in the context of p53 deficiency remains an open question, although some clues may be emerging. 53BP1 has been reported to interact with Cdc27, a component of the anaphase-promoting complex (34). Intriguingly, the Artemis-related protein Snm1 has also been reported to associate with 53BP1 and coimmunoprecipitates with Cdc27 (31,35).…”

Section: Discussionmentioning

confidence: 99%

53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis

Morales

Franco

Murphy

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

p53-binding protein 1 (53BP1) participates in the cellular response to DNA double-stranded breaks where it associates with various DNA repair͞cell cycle factors including the H2AX histone variant. Mice deficient for 53BP1 (53BP1 ؊/؊ ) are sensitive to ionizing radiation and immunodeficient because of impaired Ig heavy chain class switch recombination. Here we show that, as compared with p53 ؊/؊ mice, 53BP1 ؊/؊ ͞p53 ؊/؊ animals more rapidly develop tumors, including T cell lymphomas and, at lower frequency, B lineage lymphomas, sarcomas, and teratomas. In addition, T cells from animals deficient for both 53BP1 and p53 (53BP1 ؊/؊ ͞p53 ؊/؊ ) display elevated levels of genomic instability relative to T cells deficient for either 53BP1 or p53 alone. In contrast to p53 ؊/؊ T cell lymphomas, which routinely display aneuploidy but not translocations, 53BP1 ؊/؊ ͞p53 ؊/؊ thymic lymphomas fall into two distinct cytogenetic categories, with many harboring clonal translocations (40%) and the remainder showing aneuploidy (60%). We propose that 53BP1, in the context of p53 deficiency, suppresses T cell lymphomagenesis through its roles in both cell-cycle checkpoints and double-stranded break repair.thymic lymphoma ͉ aneuploidy ͉ translocations D ouble-stranded break (DSB) repair is essential for genomic stability and tumor suppression. In mammalian cells, DSBs arise through exogenous means such as ionizing radiation, at stalled replication forks, and in the context of two genetically programmed processes that occur in lymphoid cells (1-3). DSBs are repaired by either of two nonmutually exclusive mechanisms: homologous recombination and nonhomologous end joining. During the development of the immune system, both B and T cells assemble the exons that encode Igs and T cell receptor variable regions by means of V(D)J recombination. In addition, mature B cells can express different Ig heavy chain constant regions through a DSB-mediated process known as Ig heavy chain class switch recombination (CSR). The DSBs that initiate V(D)J recombination are generated by the site-specific RAG endonuclease, whereas those that initiate CSR appear to involve the activation-induced deaminase. However, both V(D)J recombination and CSR are completed by nonhomologous end joining. In contrast to V(D)J recombination, CSR requires components of the DNA DSB repair response, including the histone variant H2AX and p53 binding protein 1 (53BP1) (4-7), potentially to juxtapose broken DSBs for nonhomologous end joining (8). Although 53BP1 is required for joining of S regions during CSR, like H2AX, it does not appear to be absolutely required for V(D)J recombination (6, 7), perhaps because of the fact that RAG also mediates synapsis functions (8).53BP1 is phosphorylated in response to ionizing radiation, accumulates at or near sites of DNA damage, and participates in the intra S and G 2 ͞M checkpoints (reviewed in ref. 9). Accumulation of 53BP1 at sites of irradiation-induced foci depends on

show abstract

Section: Discussionmentioning

confidence: 99%

53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis

Morales

Franco

Murphy

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Higher tendency for teraploidization and for micronuclear formation is commonly reported in cells deficient in mitotic checkpoint elements, such as MAD2, Chfr and SNM1 (Scolnick and Halazonetis, 2000;Michel et al, 2001;Akhter et al, 2004) …”

Section: Nek7-negative Mefs Do Not Exhibit Metaphase Arrestmentioning

confidence: 95%

Nek7 kinase targeting leads to early mortality, cytokinesis disturbance and polyploidy

et al. 2010

View full text Add to dashboard Cite

The mammalian NIMA-related kinases (Neks) are commonly referred to as mitotic kinases, although a definitive in vivo verification of this definition is largely missing. Reduction in the activity of Nek7 or its close paralog, Nek6, has previously been shown to arrest cells in mitosis, mainly at metaphase. In this study, we investigate the developmental and cellular roles of Nek7 kinase through the generation and analysis of Nek7-deficient mice. We show that absence of Nek7 leads to lethality in late embryogenesis or at early post-natal stages and to severe growth retardation. Mouse embryonic fibroblasts (MEFs) derived from Nek7 À/À embryos show increase tendency for chromosomal lagging, micronuclei formation and cytokinesis failure. Tetraploidy and aneuploidy were commonly observed and their prevalence arises with MEFs passages. The frequency of multicentrosomal cells in the mutant's MEF cells was higher, and it commonly occurred concurrently with a binuclear phenotype, suggesting cytokinesis failure etiology. Lastly, the percentage of mutant MEF cells bearing primary cilia (PC) was low, whereas a cell population having two cilia appeared in the mutant MEFs. Taken together, these results confirm Nek7 as a regulator of cell division, and reveal it as an essential component for mammalian growth and survival. The intimate connection between tetraploidy, aneuploidy and cancer development suggests that Nek7 deregulation can induce oncogenesis.

show abstract

“…However, mammalian SNM1A-deficient cells exhibit no hypersensitivity to IR and only a modest hypersensitivity to interstrand cross-linking agents (Dronkert et al, 2000;Ahkter et al, 2005), although sensitivity to cisplatin has been observed in chicken DT40 cells (Ishiai et al, 2004;Nojima et al, 2005). Intriguingly, Snm1A-deficient mouse embryonic fibroblasts are highly sensitive to spindle poisons such as nocodazole and taxol, and Snm1A has been shown to be involved in an early mitotic checkpoint pathway in response to these drugs (Akhter et al, 2004). This mitotic checkpoint pathway appears to be congruent with that involving the Chfr tumor suppressor gene (Scolnick and Halazonetis, 2000;Chaturvedi et al, 2002;Matsusaka and Pines, 2004;Summers et al, 2005;Yu et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Snm1B/Apollo mediates replication fork collapse and S Phase checkpoint activation in response to DNA interstrand cross-links

et al. 2008

View full text Add to dashboard Cite

The removal of DNA interstrand cross-links (ICLs) has proven to be notoriously complicated due to the involvement of multiple pathways of DNA repair, which include the Fanconi anemia/BRCA pathway, homologous recombination and components of the nucleotide excision and mismatch repair pathways. Members of the SNM1 gene family have also been shown to have a role in mediating cellular resistance to ICLs, although their precise function has remained elusive. Here, we show that knockdown of Snm1B/Apollo in human cells results in hypersensitivity to mitomycin C (MMC), but not to IR. We also show that Snm1B-deficient cells exhibit a defective S phase checkpoint in response to MMC, but not to IR, and this finding may account for the specific sensitivity to the cross-linking drug. Interestingly, although previous studies have largely implicated ATR as the major kinase activated in response to ICLs, we show that it is activation of the ATMmediated checkpoint that is defective in Snm1B-deficient cells. The requirement for Snm1B in ATM checkpoint activation specifically after ICL damage is correlated with its role in promoting double-strand break formation, and thus replication fork collapse. Consistent with this result Snm1B was found to interact directly with Mus81-Eme1, an endonuclease previously implicated in fork collapse. In addition, we also show that Snm1B interacts with the Mre11-Rad50-Nbs1 (MRN) complex and with FancD2 further substantiating its role as a checkpoint/DNA repair protein.

show abstract

Deficiency in SNM1 Abolishes an Early Mitotic Checkpoint Induced by Spindle Stress

Cited by 30 publications

References 40 publications

53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis

53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis

Nek7 kinase targeting leads to early mortality, cytokinesis disturbance and polyploidy

Snm1B/Apollo mediates replication fork collapse and S Phase checkpoint activation in response to DNA interstrand cross-links

Contact Info

Product

Resources

About