FIG 2 - uploaded by Cheen Fei Chin
Content may be subject to copyright.
Key players at the antephase checkpoint. As cells progress from G 2 into mitosis, there is a phase between these phases called antephase where chromosome condensation is reversible. The antephase appears to depend upon both p38 and CHFR for reversing chromosome condensation when the cells are exposed to stress agents, including spindle damage and low temperature.
Source publication
Maintenance of genomic stability is needed for cells to survive many rounds of division throughout their lifetime. Key to
the proper inheritance of intact genome is the tight temporal and spatial coordination of cell cycle events. Moreover, checkpoints
are present that function to monitor the proper execution of cell cycle processes. For instance,...
Context in source publication
Context 1
... which is a prelude to malignant tumor formation (56). To date, two complexes, condensins I and II, are known to be involved in chromosome condensation. The eventual targets of the an- tephase checkpoint are likely the condensin complexes, but of these two complexes, which is the more important during checkpoint activation remains to be seen (Fig. ...
Citations
... The human cell is subject to approximately 50,000 DNA lesions per day, the majority of these being single-stranded or DSBs [55][56][57]. Immediately, cells with DSB activate the DDR signal, and many proteins involved in DSB processing and repair accumulate in the damaged area. DSBs are revealed by the Mre11-Rad50-Nbs1 (MRN) and Ku70-Ku80 The newly discovered field of translesion synthesis (TLS) has suggested that mammalian cells need distinct polymerases to efficiently and accurately bypass DNA lesions. ...
... The human cell is subject to approximately 50,000 DNA lesions per day, the majority of these being single-stranded or DSBs [55][56][57]. Immediately, cells with DSB activate the DDR signal, and many proteins involved in DSB processing and repair accumulate in the damaged area. DSBs are revealed by the Mre11-Rad50-Nbs1 (MRN) and Ku70-Ku80 complexes, which in turn recruit ATM and DNA-dependent protein kinase catalytic subunit (DNA-PKcs), respectively [58,59]. ...
... DSBs are revealed by the Mre11-Rad50-Nbs1 (MRN) and Ku70-Ku80 complexes, which in turn recruit ATM and DNA-dependent protein kinase catalytic subunit (DNA-PKcs), respectively [58,59]. Mostly, the target is the C terminus of the histone variant H2AX, whose derivative phosphorylated on serine 139 (S139) is referred to as γH2AX [55][56][57]. Then, γH2AX is boundby the tandem BRCA1 C-terminal domain (BRCT) domain of the DDR mediator protein MDC1 (mediator of DNA damage checkpoint 1). ...
Variation in chromosome structure is a central source of DNA damage and DNA damage response, together representinga major hallmark of chromosomal instability. Cancer cells under selective pressure of therapy use DNA damage and DNA damage response to produce newfunctional assets as an evolutionary mechanism. Recent efforts to understand DNA damage/chromosomal instability and elucidate its role in initiation or progression of cancer have also disclosed its vulnerabilities represented by inappropriate DNA damage response, chromatin changes, andinflammation. Understanding these vulnerabilities can provide important clues for predicting treatment response and for the development of novel strategies that prevent the emergence of therapy resistant tumors.
... Maximum inhibitory level was recorde in cells treated with 1% concentration of gel extraction at 4 hours treatment. The decrease in cell division rate is evidence of linseed anti mitotic potential and genotoxicity that led to arrest the cell cycle progression in treated [11], [13], [14], [15]. ...
Article information This study was conducted at Misurata City in Libya. Gel of linseed is primary a mixture of polysacharies which acid-catalyzed hydrolysis yield rhamonose fucose arabinose, xylose, glactose, galacturonic acide, and glucose. It used as an emulsifying agent for chocolate milk and functionally resembles arbic gum. In this study gel of linseed isolated from locally, Linseeds by hot water extract. Antimitotic action potential of extracted gel investigated using Allium cepa bioassay. Different concentration of gel (2.5%, 5%) were tested at different periods (2, 4, 6hours) on active growing root tip cells .Changes in the rate of cell division (mitotic index) was recorded. The result showed a significant decrease in mitotic index in treated cells in comparison with control. The result showed also that gel of linseed has more mitodepressant action than whole seed extract. IR of the extracted gel and whole seed extract were similar in band number and peaks. The data suggest that mitodepressnt effect of Linseed gel on rate of cell division may result of biologically active functional group of chemicals indicated by absorption spectra properties.
... PARP-1 is accumulated in the centrosome chromatin until metaphase during mitosis and dissociates from anaphase after interacting with centromere proteins A and B and BUB mitotic checkpoint proteins[15, 68,70]. It has also been found to interact with aurora kinases to inhibit DNA damage-induced activity and reduce histone H3 serine 10 phosphorylation [71]. Furthermore, another mitotic checkpoint, known as the antephase checkpoint, precedes the spindle assembly checkpoint and occurs in the initial prophase [72]. ...
... The key function of CHFR is to ensure intact antephase checkpoints, and it has been demonstrated that PARylation increases interaction with CHFR to control prophase checkpoints in stressful environments during mitosis [70,73,74]. It is likely for listed genes to be potential candidates to be targeted for demonstrating the association of mitosis defects with PARP-1 and PARylation in identifying the malignancy of CRC [60,[63][64][65][66]68,69,[71][72][73][74]. ...
The development of colorectal cancer (CRC) can result from changes in a variety of cellular systems within the tumor microenvironment. Particularly, it is primarily associated with genomic instability that is the gradual accumulation of genetic and epigenetic changes consisting of a characteristic set of mutations crucial for pathways in CRC progression. Based on this background, the potential to focus on poly [adenosine diphosphate (ADP)-ribose] polymerase (PARP)-1 and poly-ADP ribosylation (PARylation) as the main causes of malignant formation of CRC may be considered. One of the important functions of PARP-1 and PARylation is its deoxyribonucleic acid (DNA) repair function, which plays a pivotal role in the DNA damage response and prevention of DNA damage maintaining the redox homeostasis involved in the regulation of oxidation and superoxide. PARP-1 and PARylation can also alter epigenetic markers and chromatin structure involved in transcriptional regulation for the oncogenes or tumor suppressor genes by remodeling histone and chromatin enzymes. Given the high importance of these processes in CRC, it can be considered that PARP-1 and PARylation are at the forefront of the pathological changes required for CRC progression. Therefore, this review addresses the current molecular biological features for understanding the multifactorial function of PARP-1 and PARylation in CRC related to the aforementioned roles; furthermore, it presents a summary of recent approaches with PARP-1 inhibition in non-clinical and clinical studies targeting CRC. This understanding could help embrace the importance of targeting PARP-1 and PARylation in the treatment of CRC, which may present the potential to identify various research topics that can be challenged both non-clinically and clinically.
... Cells irradiated in mitosis were shown to have the lowest colony-forming capacity, followed by cells in S phase, indicating that these two cell-cycle phases are relatively sensitive to DSBs (Figure 3). More recently, it was shown that also during antephase, a short period in late G2 and/or early prophase before cells irreversibly commit to mitosis (Chin and Yeong, 2010), cells are hypersensitive to DSBs (Feringa et al., 2016). As a result, antephase cells exit the cell cycle in response to very low numbers of DSBs (Feringa et al., 2016). ...
DNA double-strand breaks (DSBs) pose a constant threat to genomic integrity. Such DSBs need to be repaired to preserve homeostasis at both the cellular and organismal levels. Hence, the DNA damage response (DDR) has evolved to repair these lesions and limit their toxicity. The initiation of DNA repair depends on the activation of the DDR, and we know that the strength of DDR signaling may differentially affect cellular viability. However, we do not fully understand what determines the cytotoxicity of a DSB. Recent work has identified genomic location, (in)correct DNA repair pathway usage, and cell-cycle position as contributors to DSB-induced cytotoxicity. In this review, we discuss how these determinants affect cytotoxicity, highlight recent discoveries, and identify open questions that could help to improve our understanding about cell fate decisions after a DNA DSB.
... Another mitotic checkpoint called the antephase checkpoint precedes the SAC and occurs in early prophase. The antephase checkpoint responds to microtubule poisons or DNA damage and elicits chromosome decondensation and mitotic delay [103]. The main antephase checkpoint protein CHFR (checkpoint with FHA and RING finger domains) is an E3 ubiquitin ligase that ubiquitinates Aurora A and PLK1 to halt mitotic progression [104,105]. ...
Mitosis ensures accurate segregation of duplicated DNA through tight regulation of chromosome condensation, bipolar spindle assembly, chromosome alignment in the metaphase plate, chromosome segregation and cytokinesis. Poly(ADP-ribose) polymerases (PARPs), in particular PARP1, PARP2, PARP3, PARP5a (TNKS1), as well as poly(ADP-ribose) glycohydrolase (PARG), regulate different mitotic functions, including centrosome function, mitotic spindle assembly, mitotic checkpoints, telomere length and telomere cohesion. PARP depletion or inhibition give rise to various mitotic defects such as centrosome amplification, multipolar spindles, chromosome misalignment, premature loss of cohesion, metaphase arrest, anaphase DNA bridges, lagging chromosomes, and micronuclei. As the mechanisms of PARP1/2 inhibitor-mediated cell death are being progressively elucidated, it is becoming clear that mitotic defects caused by PARP1/2 inhibition arise due to replication stress and DNA damage in S phase. As it stands, entrapment of inactive PARP1/2 on DNA phenocopies replication stress through accumulation of unresolved replication intermediates, double-stranded DNA breaks (DSBs) and incorrectly repaired DSBs, which can be transmitted from S phase to mitosis and instigate various mitotic defects, giving rise to both numerical and structural chromosomal aberrations. Cancer cells have increased levels of replication stress, which makes them particularly susceptible to a combination of agents that compromise replication fork stability. Indeed, combining PARP1/2 inhibitors with genetic deficiencies in DNA repair pathways, DNA-damaging agents, ATR and other cell cycle checkpoint inhibitors has yielded synergistic effects in killing cancer cells. Here I provide a comprehensive overview of the mitotic functions of PARPs and PARG, mitotic phenotypes induced by their depletion or inhibition, as well as the therapeutic relevance of targeting mitotic cells by directly interfering with mitotic functions or indirectly through replication stress.
... The Saccharomyces cerevisiae proteins Dma1 and Dma2 mediate the spindle positioning checkpoint and regulate septin disassembly at the end of mitosis Fraschini et al., 2004;Merlini et al., 2012). A key component of the antephase checkpoint, CHFR delays metaphase entry upon mitotic spindle stress (Burgess et al., 2008;Chin and Yeong, 2010;Matsusaka and Pines, 2004;Scolnick and Halazonetis, 2000), and similarly to Dma1, it could potentially exert this effect via Plk1 (Kang et al., 2002;Kim et al., 2011;Shtivelman, 2003;Yu et al., 2005). RNF8, another human FHA-RING ligase, antagonizes mitotic exit Plans et al., 2008;Tuttle et al., 2007) and has additional functions in protecting against DNA double strand breaks, replication stress, and genomic instability (Halaby et al., 2013;Sy et al., 2011). ...
During cell division, the timing of mitosis and cytokinesis must be ordered to ensure that each daughter cell receives a complete, undamaged copy of the genome. In fission yeast, the septation initiation network (SIN) is responsible for this coordination, and a mitotic checkpoint dependent on the E3 ubiquitin ligase Dma1 and the protein kinase CK1 controls SIN signaling to delay cytokinesis when there are errors in mitosis. The participation of kinases and ubiquitin ligases in cell cycle checkpoints that maintain genome integrity is conserved from yeast to human, making fission yeast an excellent model system in which to study checkpoint mechanisms. In this review, we highlight recent advances and remaining questions related to checkpoint regulation, which requires the synchronized modulation of protein ubiquitination, phosphorylation, and subcellular localization.
... Las células de los vertebrados no solo pueden retrasar la mitosis (Tuttle et al., 2007), sino revertirla (Chin y Yeong, 2010). En particular, la proteína RNF8 participa activamente en el control del ciclo celular, sus principales funciones las realiza durante la mitosis tardía y la fase G2/M; se propone que durante la mitosis tardía RNF8 prepara los sitios de unión de 53BP1 en la cromatina al iniciar G1 (Doil et al., 2009;Giunta et al., 2010). ...
... En particular, la proteína RNF8 participa activamente en el control del ciclo celular, sus principales funciones las realiza durante la mitosis tardía y la fase G2/M; se propone que durante la mitosis tardía RNF8 prepara los sitios de unión de 53BP1 en la cromatina al iniciar G1 (Doil et al., 2009;Giunta et al., 2010). RNF8 es requerido durante la fase G2/M para controlar la sensibilidad a las radiaciones ionizantes y evitar el avance a la fase M de células dañadas (Huen et al., 2007;Kolas et al., 2007), si este daño es detectado, la célula es capaz de revertir la compactación de los cromosomas a la fase G2 hasta corregir el defecto (Chin y Yeong, 2010). Se ha observado que la sobrexpresión de RNF8 retrasa la citoquinesis y provoca la aparición de figuras mitóticas aberrantes (Plans et al., 2008). ...
RESUMEN El cáncer de mama hereditario se ha asociado con alteraciones en el gen BRCA1, imposibilitando a la célula tumoral reparar las lesiones de doble cadena del ADN por recombinación homóloga. En la célula normal la RH es nece-saria para el mantenimiento de la integridad del ADN. Sin embargo, en las células con BRCA1 disfuncional, el ADN es reparado por el sistema de unión de extremos no homólogos propenso a errores en la reparación del ADN. Esta condición involucra a 53BP1, cuya función es esencial para el sistema UENH, favoreciendo la inestabilidad genómica y la tum-origénesis mamaria. RNF8 es una E3 ubiquitina ligasa que promueve el enlace de BRCA1 y 53BP1 ubicándolas en los sitios de ADN dañado. Se presentan una serie de alternativas con el objetivo de reconocer y promover la eliminación de RNF8. Estas aproximaciones presentan a RNF8 como blanco en estrategias farmacológicas para eliminar la inestabilidad genómica dependiente de 53BP1 y la resistencia farma-cológica promovida por la inactivación de 53BP1 en células mamarias carentes de BRCA1. Palabras clave: 53bp1, brca1, rnf8, cáncer de mama. ABSTRACT Hereditary breast cancer has been associated with alterations in the BRCA1 gene, making it impossible to repair DNA double-strand breaks by homologous recombination. This condition involves 53BP1, frequently altered in cancer, which function is essential for the non-homologous end joining mechanism, promoting genomic instability and mam-mary tumorigenesis. RNF8 is an E3 ubiquitin-protein ligase whose function promotes the binding of BRCA1 and 53BP1 locating them at sites of DNA damage. Some approaches are presented with the aim to recognize and promote the elimination of RNF8, which could be used as a pharmacological strategy to eliminate both the 53BP1-dependent genomic instability and drug resistance promoted by its inactivation in BRCA1-deficient mammary cells.
... Fourth, cells have several mechanisms to respond to injury or DNA damage, which might eventually alter proteins and pathways, including apoptosis, cycle arrest, autophagy, or protein synthesis shutoff [38]. Fifth, key cellular processes have numerous controls that tightly regulate their activity, such as delay of cell cycle progression during mitosis in the presence of DNA or spindle damage [39,40]. Finally, the immune system is a final supervisory system of error correction by destroying cells with disordered properties [41]. ...
Background: Current biologic research is based on reductionism, through which organisms and cells are merely combinations of simpler systems. However this approach has failed to substantially reduce cancer-related deaths. Complexity theory suggests that emergent properties, based on unpredictable, nonlinear interactions between the parts, are important in understanding fundamental features of systems with large numbers of independent agents, such as living systems. Methods and Findings: The laws of complexity and self-organization are summarized and applied to neoplasia: 1.In life, as in other complex systems, the whole is greater than the sum of the parts.2.There is an inherent inability to predict the future of complex systems.3.Life emerges from non-life when the diversity of a closed system of biomolecules exceeds a threshold of complexity.4.Much of the order in organisms is due to generic network properties.5.Numerous biologic pressures push cellular pathways towards disorder.6.Organisms resist common pressures towards disorder through multiple layers of redundant controls, many related to cell division.7.Neoplasia arises due to failure in these controls, with histologic and molecular characteristics related to the cell of origin, the nature of the biologic pressures and the individual’s germline configuration. Conclusions: Cells maintain order by redundant control features that resist inherent biologic pressures towards disorder. Neoplasia is due to the accumulation of changes that undermine these controls. Studying neoplasia within this context may generate new therapeutic approaches by focusing on the underlying pressures on cellular networks. An expanded version of this paper is available at http://natpernick.com/TheLawsJune2017.pdf.
... In addition, the RC itself could lead to slower cell division. There are several possible reasons for reduced cell growth, and one of them is chromosome condensation delay at the antephase checkpoint (Chin and Yeong 2010). ...
Ring chromosomes (RCs) are circular DNA molecules, which occur rarely in eukaryotic nuclear genomes. Lilian Vaughan Morgan first described them in the fruit fly. Human embryos very seldom have RCs, about 1:50,000. Carriers of RCs may have varying degrees of symptoms, from healthy phenotype to serious pathologies in physical and intellectual development. Many authors describe common symptoms of RC presence: short stature and some developmental delay that could be described as a “ring chromosome syndrome.” As a rule, RCs arise de novo through the end-joining of two DNA double-strand breaks, telomere-subtelomere junction, or inv dup del rearrangement in both meiosis and mitosis. There are family cases of RC inheritance. The presence of RCs causes numerous secondary chromosome rearrangements in vivo and in vitro. RCs can change their size, become lost, or increase their copy number and cause additional deletions, duplication, and translocations, affecting both RCs and other chromosomes. In this review, we examine RC inheritance, instability, mechanisms of formation, and potential clinical applications of artificially created RCs for large-scale chromosome rearrangement treatment.
... Las células de los vertebrados no solo pueden retrasar la mitosis (Tuttle et al., 2007), sino revertirla (Chin y Yeong, 2010). En particular, la proteína RNF8 participa activamente en el control del ciclo celular, sus principales funciones las realiza durante la mitosis tardía y la fase G2/M; se propone que durante la mitosis tardía RNF8 prepara los sitios de unión de 53BP1 en la cromatina al iniciar G1 (Doil et al., 2009;Giunta et al., 2010). ...
... En particular, la proteína RNF8 participa activamente en el control del ciclo celular, sus principales funciones las realiza durante la mitosis tardía y la fase G2/M; se propone que durante la mitosis tardía RNF8 prepara los sitios de unión de 53BP1 en la cromatina al iniciar G1 (Doil et al., 2009;Giunta et al., 2010). RNF8 es requerido durante la fase G2/M para controlar la sensibilidad a las radiaciones ionizantes y evitar el avance a la fase M de células dañadas (Huen et al., 2007;Kolas et al., 2007), si este daño es detectado, la célula es capaz de revertir la compactación de los cromosomas a la fase G2 hasta corregir el defecto (Chin y Yeong, 2010). Se ha observado que la sobrexpresión de RNF8 retrasa la citoquinesis y provoca la aparición de figuras mitóticas aberrantes (Plans et al., 2008). ...
El cáncer de mama hereditario se ha asociado con alteraciones en el gen BRCA1, imposibilitando a la célula tumoral reparar las lesiones de doble cadena del ADN por recombinación homóloga. En la célula normal la RH es necesaria para el mantenimiento de la integridad del ADN. Sin embargo, en las células con BRCA1 disfuncional, el ADN es reparado por el sistema de unión de extremos no homólogos propenso a errores en la0reparación del ADN. Esta condición involucra a 53BP1, cuya función es esencial para el sistema UENH, favoreciendo la inestabilidad genómica y la tumorigénesis mamaria. RNF8 es una E3 ubiquitina ligasa que promueve el enlace de BRCA1 y 53BP1 ubicándolas en los sitios de ADN dañado. Se presentan una serie de alternativas con el objetivo de reconocer y promover la eliminación de RNF8. Estas aproximaciones presentan a RNF8 como blanco en estrategias farmacológicas para eliminar la inestabilidad genómica dependiente de 53BP1 y la resistencia farmacológica promovida por la inactivación de 53BP1 en células mamarias carentes de BRCA1.
