scholarly journals Oncogenic RAS Induces Accelerated Transition through G2/M and Promotes Defects in the G2 DNA Damage and Mitotic Spindle Checkpoints

2006 ◽  
Vol 281 (7) ◽  
pp. 3800-3809 ◽  
Author(s):  
Jeffrey A. Knauf ◽  
Bin Ouyang ◽  
Erik S. Knudsen ◽  
Kenji Fukasawa ◽  
George Babcock ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mitotic Spindle ◽  
Oncogenic Ras ◽  
Spindle Checkpoints

scholarly journals BRG1 Is Required for Formation of Senescence-Associated Heterochromatin Foci Induced by Oncogenic RAS or BRCA1 Loss

2013 ◽  
Vol 33 (9) ◽  
pp. 1819-1829 ◽  
Author(s):  
Zhigang Tu ◽  
Xinying Zhuang ◽  
Yong-Gang Yao ◽  
Rugang Zhang
Keyword(s):  
Dna Damage ◽  
Molecular Mechanism ◽  
Chromatin Remodeling ◽  
Cellular Senescence ◽  
Chromatin Immunoprecipitation ◽  
Tumor Suppression ◽  
Gene Promoters ◽  
Independent Manner ◽  
Oncogenic Ras ◽  
Suppression Mechanism

Cellular senescence is an important tumor suppression mechanism. We have previously reported that both oncogene-induced dissociation of BRCA1 from chromatin and BRCA1 knockdown itself drive senescence by promoting formation of s enescence- a ssociated h eterochromatin f oci (SAHF). However, the molecular mechanism by which BRCA1 regulates SAHF formation and senescence is unclear. BRG1 is a chromatin-remodeling factor that interacts with BRCA1 and pRB. Here we show that BRG1 is required for SAHF formation and senescence induced by oncogenic RAS or BRCA1 loss. The interaction between BRG1 and BRCA1 is disrupted during senescence. This correlates with an increased level of chromatin-associated BRG1 in senescent cells. BRG1 knockdown suppresses the formation of SAHF and senescence, while it has no effect on BRCA1 chromatin dissociation induced by oncogenic RAS, indicating that BRG1 functions downstream of BRCA1 chromatin dissociation. Furthermore, BRG1 knockdown inhibits SAHF formation and senescence induced by BRCA1 knockdown. Conversely, BRG1 overexpression drives SAHF formation and senescence in a DNA damage-independent manner. This effect depends upon BRG1's chromatin-remodeling activity as well as the interaction between BRG1 and pRB. Indeed, the interaction between BRG1 and pRB is enhanced during senescence. Chromatin immunoprecipitation analysis revealed that BRG1's association with the human CDKN2A and CDKN1A gene promoters was enhanced during senescence induced by oncogenic RAS or BRCA1 knockdown. Consistently, knockdown of pRB, p21 CIP1 , and p16 INK4a , but not p53, suppressed SAHF formation induced by BRG1. Together, these studies reveal the molecular underpinning by which BRG1 acts downstream of BRCA1 to promote SAHF formation and senescence.

Abstract A68: MCT-1 oncoprotein induces chromosomal aberrations through impairing centrosomal and mitotic-spindle checkpoints.

2011 ◽  
Author(s):  
Yen-An Chen ◽  
Hung-Ju Shih ◽  
Kang-Lin Chu ◽  
Chik-On Choy ◽  
Pei-Hsuan Wu ◽  
...  
Keyword(s):  
Chromosomal Aberrations ◽  
Mitotic Spindle ◽  
Spindle Checkpoints

scholarly journals Mitotic spindle defects and DNA damage induced by dimethoxycurcumin lead to an intrinsic apoptosis pathway in HepG2/C3A cells

2019 ◽  
Vol 61 ◽  
pp. 104643 ◽  
Author(s):  
Thalita Alves Zanetti ◽  
Bruna Isabela Biazi ◽  
Giuliana Castello Coatti ◽  
Adrivanio Baranoski ◽  
Lilian Areal Marques ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mitotic Spindle ◽  
Intrinsic Apoptosis ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

scholarly journals p53 mitotic centrosome localization preserves centrosome integrity and works as sensor for the mitotic surveillance pathway

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Claudia Contadini ◽  
Laura Monteonofrio ◽  
Ilaria Virdia ◽  
Andrea Prodosmo ◽  
Davide Valente ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Cells ◽  
Mitotic Spindle ◽  
Human Cells ◽  
Genome Integrity ◽  
Specific Behavior ◽  
Spindle Formation ◽  
Mouse Cells ◽  
Species Specific ◽  
Selective Impairment

Abstract Centrosomal p53 has been described for three decades but its role is still unclear. We previously reported that, in proliferating human cells, p53 transiently moves to centrosomes at each mitosis. Such p53 mitotic centrosome localization (p53-MCL) occurs independently from DNA damage but requires ATM-mediated p53Ser15 phosphorylation (p53Ser15P) on discrete cytoplasmic p53 foci that, through MT dynamics, move to centrosomes during the mitotic spindle formation. Here, we show that inhibition of p53-MCL, obtained by p53 depletion or selective impairment of p53 centrosomal localization, induces centrosome fragmentation in human nontransformed cells. In contrast, tumor cells or mouse cells tolerate p53 depletion, as expected, and p53-MCL inhibition. Such tumor- and species-specific behavior of centrosomal p53 resembles that of the recently identified sensor of centrosome-loss, whose activation triggers the mitotic surveillance pathway in human nontransformed cells but not in tumor cells or mouse cells. The mitotic surveillance pathway prevents the growth of human cells with increased chance of making mitotic errors and accumulating numeral chromosome defects. Thus, we evaluated whether p53-MCL could work as a centrosome-loss sensor and contribute to the activation of the mitotic surveillance pathway. We provide evidence that centrosome-loss triggered by PLK4 inhibition makes p53 orphan of its mitotic dock and promotes accumulation of discrete p53Ser15P foci. These p53 foci are required for the recruitment of 53BP1, a key effector of the mitotic surveillance pathway. Consistently, cells from patients with constitutive impairment of p53-MCL, such as ATM- and PCNT-mutant carriers, accumulate numeral chromosome defects. These findings indicate that, in nontransformed human cells, centrosomal p53 contributes to safeguard genome integrity by working as sensor for the mitotic surveillance pathway.

scholarly journals Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence

Oncogene ◽  
2010 ◽  
Vol 30 (12) ◽  
pp. 1489-1496 ◽  
Author(s):  
P Rai ◽  
J J Young ◽  
D G A Burton ◽  
M G Giribaldi ◽  
T T Onder ◽  
...  
Keyword(s):  
Dna Damage ◽  
Guanine Nucleotides ◽  
Premature Senescence ◽  
Oncogenic Ras ◽  
Oxidized Guanine

scholarly journals CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response

2010 ◽  
Vol 189 (1) ◽  
pp. 23-39 ◽  
Author(s):  
Alexis R. Barr ◽  
John V. Kilmartin ◽  
Fanni Gergely
Keyword(s):  
Dna Damage ◽  
Cell Fate ◽  
Mitotic Spindle ◽  
Brain Size ◽  
Neurodevelopmental Disorder ◽  
Spindle Pole ◽  
Spindle Positioning ◽  
Dna Damage Signaling ◽  
Spindle Poles ◽  
G2 Cell Cycle Arrest

The centrosomal protein, CDK5RAP2, is mutated in primary microcephaly, a neurodevelopmental disorder characterized by reduced brain size. The Drosophila melanogaster homologue of CDK5RAP2, centrosomin (Cnn), maintains the pericentriolar matrix (PCM) around centrioles during mitosis. In this study, we demonstrate a similar role for CDK5RAP2 in vertebrate cells. By disrupting two evolutionarily conserved domains of CDK5RAP2, CNN1 and CNN2, in the avian B cell line DT40, we find that both domains are essential for linking centrosomes to mitotic spindle poles. Although structurally intact, centrosomes lacking the CNN1 domain fail to recruit specific PCM components that mediate attachment to spindle poles. Furthermore, we show that the CNN1 domain enforces cohesion between parental centrioles during interphase and promotes efficient DNA damage–induced G2 cell cycle arrest. Because mitotic spindle positioning, asymmetric centrosome inheritance, and DNA damage signaling have all been implicated in cell fate determination during neurogenesis, our findings provide novel insight into how impaired CDK5RAP2 function could cause premature depletion of neural stem cells and thereby microcephaly.

scholarly journals Mdb1, a Fission Yeast Homolog of Human MDC1, Modulates DNA Damage Response and Mitotic Spindle Function

PLoS ONE ◽  
2014 ◽  
Vol 9 (5) ◽  
pp. e97028 ◽  
Author(s):  
Yi Wei ◽  
Hai-Tao Wang ◽  
Yonggong Zhai ◽  
Paul Russell ◽  
Li-Lin Du
Keyword(s):  
Dna Damage ◽  
Fission Yeast ◽  
Dna Damage Response ◽  
Mitotic Spindle ◽  
Damage Response ◽  
Spindle Function ◽  
Yeast Homolog

scholarly journals C/EBPβ represses p53 to promote cell survival downstream of DNA damage independent of oncogenic Ras and p19Arf

2008 ◽  
Vol 15 (11) ◽  
pp. 1734-1744 ◽  
Author(s):  
S J Ewing ◽  
S Zhu ◽  
F Zhu ◽  
J S House ◽  
R C Smart
Keyword(s):  
Dna Damage ◽  
Cell Survival ◽  
Oncogenic Ras ◽  
Promote Cell Survival

scholarly journals Centromere-localized breaks indicate the generation of DNA damage by the mitotic spindle

2010 ◽  
Vol 107 (9) ◽  
pp. 4159-4164 ◽  
Author(s):  
A. A. Guerrero ◽  
M. C. Gamero ◽  
V. Trachana ◽  
A. Futterer ◽  
C. Pacios-Bras ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mitotic Spindle
Sign in / Sign up

Export Citation Format

Share Document