A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage

Nature ◽  
2000 ◽  
Vol 404 (6773) ◽  
pp. 42-49 ◽  
Author(s):  
Hiroshi Tanaka ◽  
Hirofumi Arakawa ◽  
Tatsuya Yamaguchi ◽  
Kenji Shiraishi ◽  
Seisuke Fukuda ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Ribonucleotide Reductase ◽  
Cell Cycle Checkpoint ◽  
Reductase Gene ◽  
Cycle Checkpoint ◽  
Dependent Cell

scholarly journals Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 750
Author(s):  
Kiyohiro Ando ◽  
Akira Nakagawara
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Mitotic Catastrophe ◽  
Malignant Neoplasms ◽  
Checkpoint Kinases ◽  
Molecular Features ◽  
Cycle Checkpoint

Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

scholarly journals PEA15 Regulates the DNA Damage-Induced Cell Cycle Checkpoint and Oncogene-Directed Transformation

2014 ◽  
Vol 34 (12) ◽  
pp. 2264-2282 ◽  
Author(s):  
A. Nagarajan ◽  
S. K. Dogra ◽  
A. Y. Liu ◽  
M. R. Green ◽  
N. Wajapeyee
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Checkpoint ◽  
Cycle Checkpoint ◽  
Directed Transformation

DNA damage checkpoint kinases in cancer

2020 ◽  
Vol 22 ◽  
Author(s):  
Hannah L. Smith ◽  
Harriet Southgate ◽  
Deborah A. Tweddle ◽  
Nicola J. Curtin
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Environmental Dna ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Control ◽  
Integrated Network ◽  
Checkpoint Kinases ◽  
G1 Checkpoint ◽  
Cycle Checkpoint ◽  
High Level

Abstract DNA damage response (DDR) pathway prevents high level endogenous and environmental DNA damage being replicated and passed on to the next generation of cells via an orchestrated and integrated network of cell cycle checkpoint signalling and DNA repair pathways. Depending on the type of damage, and where in the cell cycle it occurs different pathways are involved, with the ATM-CHK2-p53 pathway controlling the G1 checkpoint or ATR-CHK1-Wee1 pathway controlling the S and G2/M checkpoints. Loss of G1 checkpoint control is common in cancer through TP53, ATM mutations, Rb loss or cyclin E overexpression, providing a stronger rationale for targeting the S/G2 checkpoints. This review will focus on the ATM-CHK2-p53-p21 pathway and the ATR-CHK1-WEE1 pathway and ongoing efforts to target these pathways for patient benefit.

scholarly journals Aberrant Expression of Nucleostemin Activates p53 and Induces Cell Cycle Arrest via Inhibition of MDM2

2008 ◽  
Vol 28 (13) ◽  
pp. 4365-4376 ◽  
Author(s):  
Mu-Shui Dai ◽  
Xiao-Xin Sun ◽  
Hua Lu
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Ribosomal Proteins ◽  
Cell Cycle Checkpoint ◽  
Aberrant Expression ◽  
Cycle Arrest ◽  
Reduce Cell Proliferation ◽  
Cycle Checkpoint ◽  
Dependent Cell

ABSTRACT The nucleolar protein nucleostemin (NS) is essential for cell proliferation and early embryogenesis. Both depletion and overexpression of NS reduce cell proliferation. However, the mechanisms underlying this regulation are still unclear. Here, we show that NS regulates p53 activity through the inhibition of MDM2. NS binds to the central acidic domain of MDM2 and inhibits MDM2-mediated p53 ubiquitylation and degradation. Consequently, ectopic overexpression of NS activates p53, induces G1 cell cycle arrest, and inhibits cell proliferation. Interestingly, the knockdown of NS by small interfering RNA also activates p53 and induces G1 arrest. These effects require the ribosomal proteins L5 and L11, since the depletion of NS enhanced their interactions with MDM2 and the knockdown of L5 or L11 abrogated the NS depletion-induced p53 activation and cell cycle arrest. These results suggest that a p53-dependent cell cycle checkpoint monitors changes of cellular NS levels via the impediment of MDM2 function.

scholarly journals Undamaged DNA Transmits and Enhances DNA Damage Checkpoint Signals in Early Embryos

2007 ◽  
Vol 27 (19) ◽  
pp. 6852-6862 ◽  
Author(s):  
Aimin Peng ◽  
Andrea L. Lewellyn ◽  
James L. Maller
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Nuclear Dna ◽  
Cell Cycle Checkpoint ◽  
Dna Damage Checkpoint ◽  
Checkpoint Signaling ◽  
Checkpoint Response ◽  
Egg Extracts ◽  
Cycle Checkpoint ◽  
Damaged Dna

ABSTRACT In Xenopus laevis embryos, the midblastula transition (MBT) at the 12th cell division marks initiation of critical developmental events, including zygotic transcription and the abrupt inclusion of gap phases into the cell cycle. Interestingly, although an ionizing radiation-induced checkpoint response is absent in pre-MBT embryos, introduction of a threshold amount of undamaged plasmid or sperm DNA allows a DNA damage checkpoint response to be activated. We show here that undamaged threshold DNA directly participates in checkpoint signaling, as judged by several dynamic changes, including H2AX phosphorylation, ATM phosphorylation and loading onto chromatin, and Chk1/Chk2 phosphorylation and release from nuclear DNA. These responses on physically separate threshold DNA require γ-H2AX and are triggered by an ATM-dependent soluble signal initiated by damaged DNA. The signal persists in egg extracts even after damaged DNA is removed from the system, indicating that the absence of damaged DNA is not sufficient to end the checkpoint response. The results identify a novel mechanism by which undamaged DNA enhances checkpoint signaling and provide an example of how the transition to cell cycle checkpoint activation during development is accomplished by maternally programmed increases in the DNA-to-cytoplasm ratio.

Dose Escalated RAD001 (Everolimus) Enhances Chemosensitivity in Precursor-B Acute Lymphoblastic Leukemia, through a JNK Dependent Suppression of Cell Cycle Checkpoint Regulation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1604-1604
Author(s):  
Philip O. Saunders ◽  
Kenneth F. Bradstock ◽  
Linda J. Bendall
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Regulation ◽  
Cell Cycle Checkpoint ◽  
G2 Arrest ◽  
Jnk Pathway ◽  
Microtubule Disruption ◽  
Cell Kill ◽  
Cycle Checkpoint ◽  
Cycle Regulation

Abstract Five year survival for patients with relapsed pre-B ALL remains less than 10%, requiring new approaches to therapy. We sought to evaluate the potential of mTOR inhibitor RAD001 to enhance pre-B ALL cell killing by agents that induce DNA damage or microtubule disruption and identify interactions that may indicate novel approaches to therapy. Combining 16μM RAD001 with agents that cause DNA damage or microtubule disruption in vitro, enhanced caspase-dependent killing (p<0.05) of pre-B ALL cells. We observed 16μM RAD001 suppressed p53 and markedly attenuated p21 responses to DNA damage or vincristine. Lentiviral siRNA knock down of p53 in Nalm6 cells led to significantly increased (p<0.05) cell kill by vincristine relative to luciferase knockdown cells with an intact p53 response. This data indicates enhanced killing by combining RAD001 with DNA damage or vincristine does not require p53. Intracellular flow cytometry revealed that combining 16μM RAD001 with DNA damage or vincristine activates the JNK pathway. c-Jun has been reported to promote proliferation, apoptosis, suppress p53 and p21 promoters and prolong the half-life of p53 analogue, p73. Concordantly, we observed up regulation of p73, puma, bax, bim and cleaved caspase 3, associated with enhanced cell death. This data indicates that p73 provides an alternate pathway to apoptosis. We hypothesized that 16μM RAD001 enhances chemosensitivity through a JNK dependent suppression of cell cycle checkpoint regulation. We observed 1.5μM RAD001 inhibited pRb, Ki67 and PCNA expression, increasing G0/1 cell cycle arrest in response to DNA damage or vincristine, however 16μM RAD001 increased pRb, cyclin D1, Ki67, active CDC2 and PCNA expression. Increased DNA content, BrdU uptake and PCNA expression indicate cell cycle progression occurs in the presence of DNA damage or vincristine, when combined with 16μM RAD001. To validate the role of the JNK pathway in enhancing chemosensitivity we evaluated the impact of JNK inhibition on cell cycle regulation and cell survival. We observed enhanced cell cycle checkpoint regulation, indicated by reduced expression of c-jun, pRb, PCNA and Ki67 in Nalm6 cells. Furthermore, JNK inhibition enhanced G0/1 or G2 arrest in response to DNA damage in Nalm6 and REH cell lines respectively and enhanced G2 arrest in response to vincristine. JNK inhibition led to reduced cell kill by DNA damage or microtubule disruption in Nalm6 and REH cell lines. This data strongly suggests that impaired cell cycle regulation by 16μM RAD001 is mediated through a JNK dependent mechanism. We conclude that dose escalated RAD001 enhances chemosensitivity independently of p53, through a JNK dependent impairment of cell cycle regulation, in response to DNA damage or microtubule disruption. Our data indicates that dose escalated RAD001 has the potential to enhance chemosensitivity in patients with pre-B ALL and provides a rationale for combining agents which induce JNK activation with DNA damage or microtubule disruption, as a therapeutic strategy in pre-B ALL.

scholarly journals Critical Role for Mouse Hus1 in an S-Phase DNA Damage Cell Cycle Checkpoint

2003 ◽  
Vol 23 (3) ◽  
pp. 791-803 ◽  
Author(s):  
Robert S. Weiss ◽  
Philip Leder ◽  
Cyrus Vaziri
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Synthesis ◽  
Critical Role ◽  
S Phase ◽  
Cell Cycle Checkpoint ◽  
Dna Damage Checkpoint ◽  
Null Mouse ◽  
Cycle Checkpoint ◽  
S Phase Checkpoint

ABSTRACT Mouse Hus1 encodes an evolutionarily conserved DNA damage response protein. In this study we examined how targeted deletion of Hus1 affects cell cycle checkpoint responses to genotoxic stress. Unlike hus1− fission yeast (Schizosaccharomyces pombe) cells, which are defective for the G2/M DNA damage checkpoint, Hus1-null mouse cells did not inappropriately enter mitosis following genotoxin treatment. However, Hus1-deficient cells displayed a striking S-phase DNA damage checkpoint defect. Whereas wild-type cells transiently repressed DNA replication in response to benzo(a)pyrene dihydrodiol epoxide (BPDE), a genotoxin that causes bulky DNA adducts, Hus1-null cells maintained relatively high levels of DNA synthesis following treatment with this agent. However, when treated with DNA strand break-inducing agents such as ionizing radiation (IR), Hus1-deficient cells showed intact S-phase checkpoint responses. Conversely, checkpoint-mediated inhibition of DNA synthesis in response to BPDE did not require NBS1, a component of the IR-responsive S-phase checkpoint pathway. Taken together, these results demonstrate that Hus1 is required specifically for one of two separable mammalian checkpoint pathways that respond to distinct forms of genome damage during S phase.

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