scholarly journals DNA damage-induced metaphase I arrest is mediated by the spindle assembly checkpoint and maternal age

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Petros Marangos ◽  
Michelle Stevense ◽  
Konstantina Niaka ◽  
Michaela Lagoudaki ◽  
Ibtissem Nabti ◽  
...  
Keyword(s):  
Dna Damage ◽  
Maternal Age ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Metaphase I

scholarly journals DNA damage induces a meiotic arrest in mouse oocytes mediated by the spindle assembly checkpoint

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Josie K. Collins ◽  
Simon I. R. Lane ◽  
Julie A. Merriman ◽  
Keith T. Jones
Keyword(s):  
Dna Damage ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Meiotic Arrest ◽  
Mouse Oocytes

scholarly journals Loss of the spectraplakin gene Short stop induces a DNA damage response in Drosophila epithelia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Evan B. Dewey ◽  
Amalia S. Parra ◽  
Christopher A. Johnston
Keyword(s):  
Dna Damage ◽  
Spindle Assembly Checkpoint ◽  
Cultured Cells ◽  
Spindle Assembly ◽  
Strand Break ◽  
Wing Disc ◽  
Tissue Type ◽  
Apoptotic Response ◽  
Jun Kinase ◽  
Jnk Activation

AbstractEpithelia are an eminent tissue type and a common driver of tumorigenesis, requiring continual precision in cell division to maintain tissue structure and genome integrity. Mitotic defects often trigger apoptosis, impairing cell viability as a tradeoff for tumor suppression. Identifying conditions that lead to cell death and understanding the mechanisms behind this response are therefore of considerable importance. Here we investigated how epithelia of the Drosophila wing disc respond to loss of Short stop (Shot), a cytoskeletal crosslinking spectraplakin protein that we previously found to control mitotic spindle assembly and chromosome dynamics. In contrast to other known spindle-regulating genes, Shot knockdown induces apoptosis in the absence of Jun kinase (JNK) activation, but instead leads to elevated levels of active p38 kinase. Shot loss leads to double-strand break (DSB) DNA damage, and the apoptotic response is exacerbated by concomitant loss of p53. DSB accumulation is increased by suppression of the spindle assembly checkpoint, suggesting this effect results from chromosome damage during error-prone mitoses. Consistent with DSB induction, we found that the DNA damage and stress response genes, Growth arrest and DNA damage (GADD45) and Apoptosis signal-regulating kinase 1 (Ask1), are transcriptionally upregulated as part of the shot-induced apoptotic response. Finally, co-depletion of Shot and GADD45 induced significantly higher rates of chromosome segregation errors in cultured cells and suppressed shot-induced mitotic arrest. Our results demonstrate that epithelia are capable of mounting molecularly distinct responses to loss of different spindle-associated genes and underscore the importance of proper cytoskeletal organization in tissue homeostasis.

scholarly journals DNA Damage during the Spindle-Assembly Checkpoint Degrades CDC25A, Inhibits Cyclin–CDC2 Complexes, and Reverses Cells to Interphase

2003 ◽  
Vol 14 (10) ◽  
pp. 3989-4002 ◽  
Author(s):  
Jeremy P.H. Chow ◽  
Wai Yi Siu ◽  
Tsz Kan Fung ◽  
Wan Mui Chan ◽  
Anita Lau ◽  
...  
Keyword(s):  
Dna Damage ◽  
Spindle Assembly Checkpoint ◽  
Histone H3 ◽  
Ectopic Expression ◽  
Spindle Assembly ◽  
Cyclin B1 ◽  
Chemotherapeutic Agents ◽  
Cell Cycle Checkpoints ◽  
Dependent Manner ◽  
Mitotic Block

Cell cycle checkpoints that monitor DNA damage and spindle assembly are essential for the maintenance of genetic integrity, and drugs that target these checkpoints are important chemotherapeutic agents. We have examined how cells respond to DNA damage while the spindle-assembly checkpoint is activated. Single cell electrophoresis and phosphorylation of histone H2AX indicated that several chemotherapeutic agents could induce DNA damage during mitotic block. DNA damage during mitotic block triggered CDC2 inactivation, histone H3 dephosphorylation, and chromosome decondensation. Cells did not progress into G1 but seemed to retract to a G2-like state containing 4N DNA content, with stabilized cyclin A and cyclin B1 binding to Thr14/Tyr15-phosphorylated CDC2. The loss of mitotic cells was not due to cell death because there was no discernible effect on caspase-3 activation, DNA fragmentation, or viability. Extensive DNA damage during mitotic block inactivated cyclin B1-CDC2 and prevented G1 entry when the block was removed. The mitotic DNA damage responses were independent of p53 and pRb, but they were dependent on ATM. CDC25A that accumulated during mitosis was rapidly destroyed after DNA damage in an ATM-dependent manner. Ectopic expression of CDC25A or nonphosphorylatable CDC2 effectively inhibited the dephosphorylation of histone H3 after DNA damage. Hence, although spindle disruption and DNA damage provide conflicting signals to regulate CDC2, the negative regulation by the DNA damage checkpoint could overcome the positive regulation by the spindle-assembly checkpoint.

scholarly journals Kinome-Wide shRNA Screen Reveals Functional Connections Between FANCA, Mitotic Centrosomes and the Spindle Assembly Checkpoint Tumor Suppressor Pathways

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3612-3612
Author(s):  
Richa Sharma ◽  
Zahi Abdul Sater ◽  
Rikki Enzor ◽  
Ying He ◽  
Grzegorz Nalepa
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Fanconi Anemia ◽  
Cross Talk ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Mitotic Checkpoint ◽  
Synthetic Lethal ◽  
Shrna Screen

Abstract Fanconi anemia (FA) is a genetic disorder characterized by progressive bone marrow failure, congenital abnormalities and predilection towards development of hematopoietic malignancies, including acute myeloid leukemia (AML). Congenital biallelic disruption of the FA/BRCA signaling network causes Fanconi anemia and somatic mutations within the same genes are increasingly identified in a variety of malignancies in non-FA individuals, consistent with the critical role of this signaling pathway in FA and in the general population. The FA/BRCA tumor suppressor network orchestrates interphase DNA-damage repair (DDR) and DNA replication to maintain genomic stability. Additionally, we and others have demonstrated that the genome housekeeping function of FA/BRCA signaling extends beyond interphase: loss of FA/BRCA signaling perturbs execution of mitosis, including the spindle assembly checkpoint (SAC), centrosome maintenance, cytokinesis and resolution of anaphase DNA bridges. Interphase errors exacerbate mitotic abnormalities and mitotic failure promotes interphase mutagenesis. Consequently, we had demonstrated that primary FA patients' cells accumulate genomic abnormalities consistent with a dual mechanism of impaired interphase DDR/replication and defective mitosis. Previous detailed studies had elucidated multiple mechanisms of interphase DDR-dependent assembly and activation of the FA complex at DNA damage sites to arrest the cell cycle and repair DNA lesions. However, the signaling cross-talk nodes between the FA and mitotic checkpoint pathways remain to be discovered. In this study, we identified functionally relevant mitotic signaling defects resulting from FANCA deficiency via a synthetic lethal kinome-wide pooled shRNA screen in primary patient-derived FANCA -deficient cells compared to isogenic FANCA -corrected cell line. Bioinformatics analysis of our screen results followed by secondary validation of selected hits with alternative shRNAs and small-molecule inhibitors revealed conserved mitotic signal transduction pathways regulating the SAC and centrosome maintenance. Our super-resolution structured illumination (SR-SIM) microscopy coupled with deconvolution imaging revealed that a fraction of FANCA co-localizes with key SAC kinases at mitotic centrosomes and kinetochores, consistent with the role of FANCA in centrosome maintenance and the SAC. Co-immunoprecipitation assays identified the biochemical interaction between FANCA and an essential SAC kinase whose loss is synthetic lethal with FANCA deficiency, providing first insights into the interactions between FA signaling and the canonical SAC network. Together, our study has unraveled functional and biochemical connections between FANCA and the centrosome/SAC kinases, consistent with the essential role of FANCA in cell division. Our ongoing work is aimed at mechanistically dissecting molecular links between these two key tumor suppressor signaling pathways in more detail. We hypothesize that impaired FANCA/SAC cross-talk may contribute to genomic instability in FA-deficient cells and provide opportunities to selectively kill FANCA-/- cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals A role for the spindle assembly checkpoint in the DNA damage response

2016 ◽  
Vol 63 (2) ◽  
pp. 275-280 ◽  
Author(s):  
Roger Palou ◽  
Gloria Palou ◽  
David G. Quintana
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Damage Response

scholarly journals DNA damage responses in mammalian oocytes

Reproduction ◽  
2016 ◽  
Vol 152 (1) ◽  
pp. R15-R22 ◽  
Author(s):  
Josie K Collins ◽  
Keith T Jones
Keyword(s):  
Dna Damage ◽  
Spindle Assembly Checkpoint ◽  
Germinal Vesicle ◽  
Spindle Assembly ◽  
Stages Of Growth ◽  
Microtubule Attachment ◽  
Dna Damage Responses ◽  
Chromosome Attachment ◽  
Spindle Microtubules ◽  
Meiosis I

DNA damage acquired during meiosis can lead to infertility and miscarriage. Hence, it should be important for an oocyte to be able to detect and respond to such events in order to make a healthy egg. Here, the strategies taken by oocytes during their stages of growth to respond to DNA damaging events are reviewed. In particular, recent evidence of a novel pathway in fully grown oocytes helps prevent the formation of mature eggs with DNA damage. It has been found that fully grown germinal vesicle stage oocytes that have been DNA damaged do not arrest at this point in meiosis, but instead undergo meiotic resumption and stall during the first meiotic division. The Spindle Assembly Checkpoint, which is a well-known mitotic pathway employed by somatic cells to monitor chromosome attachment to spindle microtubules, appears to be utilised by oocytes also to respond to DNA damage. As such maturing oocytes are arrested at metaphase I due to an active Spindle Assembly Checkpoint. This is surprising given this checkpoint has been previously studied in oocytes and considered to be weak and ineffectual because of its poor ability to be activated in response to microtubule attachment errors. Therefore, the involvement of the Spindle Assembly Checkpoint in DNA damage responses of mature oocytes during meiosis I uncovers a novel second function for this ubiquitous cellular checkpoint.

scholarly journals Aurora Kinase-A Inactivates DNA Damage-Induced Apoptosis and Spindle Assembly Checkpoint Response Functions of p73

Cancer Cell ◽  
2012 ◽  
Vol 21 (2) ◽  
pp. 196-211 ◽  
Author(s):  
Hiroshi Katayama ◽  
Jin Wang ◽  
Warapen Treekitkarnmongkol ◽  
Hidehiko Kawai ◽  
Kaori Sasai ◽  
...  
Keyword(s):  
Dna Damage ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Aurora Kinase ◽  
Response Functions ◽  
Checkpoint Response ◽  
Aurora Kinase A ◽  
Induced Apoptosis ◽  
Kinase A

A Defective Spindle Assembly Checkpoint Is Not Likely the Primary Cause of Maternal Age-Associated Aneuploidy in Mouse Eggs.

2009 ◽  
Vol 81 (Suppl_1) ◽  
pp. 177-177
Author(s):  
Francesca E. Duncan ◽  
Teresa Chiang ◽  
Michael A. Lampson ◽  
Richard M. Schultz
Keyword(s):  
Maternal Age ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Mouse Eggs
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