Toward Maintaining the Genome: DNA Damage and Replication Checkpoints

Nyberg, Kara A.; Michelson, Rhett J.; Putnam, Charles W.; Weinert, Ted

doi:10.1146/annurev.genet.36.060402.113540

Cited by 715 publications

(705 citation statements)

References 233 publications

(267 reference statements)

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“…The G 1 /S arrest is a typical response to the activation of G 1 /S checkpoint, which serves as an important defense mechanism against genomic instability, before the full commitment of cell division (Elledge, 1996;Bartek and Lukas, 2001). Therefore, we decided to investigate the response of MLL5 to the activation of G 1 /S checkpoint by stressing the cells with various DNA-damaging agents, including cisplatin, etoposide, CPT, aphidicolin (Aph) and methyl methanesulfonate (Nyberg et al, 2002). Surprisingly, the expression of MLL5 protein was almost completely abolished by CPT, but only slightly downregulated or unaffected by other DNAdamaging agents, in colorectal carcinoma HCT116 cells ( Figure 1a) and osteosarcoma U2OS cells (Supplementary Figure S1).…”

Section: Camptothecin Promotes Degradation Of Mll5mentioning

confidence: 99%

Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53

et al. 2011

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Mixed lineage leukemia 5 (MLL5) has been implicated in multiple aspects of cell physiology, such as hematopoiesis, cell cycle control and chromatin regulatory network. In this study, we present evidence that MLL5 is involved in the camptothecin (CPT)-induced p53 activation. CPT promoted the degradation of MLL5 protein in a time-and dose-dependent manner in actively replicating cells. The downregulation of MLL5 led to phosphorylation of p53 at Ser392, which was abrogated by exogenous overexpression of MLL5. In MLL5-knockdown cells, p53 protein was stabilized and bound to DNA with higher affinity, leading to activation of downstream genes. Co-immunoprecipitation showed that MLL5 preferentially interacted with the tetramerized form of p53, and knockdown of MLL5 promoted chromatin accumulation of p53 tetramers, suggesting that the association of MLL5 with p53 may prevent the p53 tetramers from binding to the chromatin target sites. The role of MLL5 in CPT-induced p53 activation was conserved in developing zebrafish, where CPT downregulated zebrafish Mll5 protein, and the microinjection of zebrafish mll5 mRNA substantially blocked the CPT-induced apoptosis. In summary, our study proposed MLL5 as a novel component in the regulation of p53 homeostasis and a new cellular determinant of CPT.

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Section: Camptothecin Promotes Degradation Of Mll5mentioning

confidence: 99%

Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53

et al. 2011

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“…S phase checkpoint slows cell cycle progression to mitosis by controlling the DNA replication machinery at stalled replication forks (Nyberg et al, 2002;Sancar et al, 2004). In contrast to the G1/S transition checkpoint, S phase checkpoint activation does not lead to a full cell cycle arrest (Rowley et al, 1999).…”

Section: S Phase Checkpointmentioning

confidence: 99%

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

Smith¹,

Dejsuphong

Balestrini³

et al. 2009

Nat Cell Biol

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The effects of ATM and ATR signalling induced by chromosomal breakage have been described extensively in modulating cell cycle progression up to the onset of mitosis.However, DNA damage checkpoint responses in mitotic cells are not well understood.This thesis reports on the effects of double strand breaks on the progression of mitosis.We found ATM and ATR activation can occur in mitotic Xenopus laevis egg extract and the induction of ATM and ATR by chromosomal breakages inhibits spindle assembly in both Xenopus egg extract and somatic cells. The delay in mitotic progression induced by ATM and ATR was found not to involve major spindle assembly factors activities such as, Cdk1, Plx1 and RCC1/Ran-GTP. However, normal anastral spindles formation around linear DNA coated beads, which can activate ATM and ATR, linked centrosome-driven spindle assembly to ATM and ATR dependent spindle defects. cDNA expression library screening was undertaken to identify novel ATM and ATR targets in this mitotic checkpoint pathway, through which the novel centrosomal protein XCEP63 was identified as a likely candidate. Data obtained from depletion and reconstitution of XCEP63 in Xenopus egg extract established that normal centrosome-driven spindle assembly requires XCEP63. Moreover, ATM and ATR phosphorylates XCEP63 on serine 560 and promotes delocalisation from the centrosome. ATM and ATR inhibition or addition of non-phosphorylable XCEP63 recombinant protein mutated at serine 560 prevents spindle assembly abnormalities.These findings suggest that ATM and ATR regulate mitotic events by targeting XCEP63 and centrosome-dependent spindle assembly. This pathway may provide support for DNA repair processes or regulate cell survival in the presence of mitotic DNA damage. 3

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“…Cell culture work has identified the kinase ATR as the central component of the S-phase checkpoint control, which upon replication stress activates other proteins in parallel to p53 (see Introduction and Nyberg et al 8 and Bartek et al 9 for reviews). We have preliminary data that in contrast to p53 itself, the ATR checkpoint control system in its entirety is required for normal cell cycle progression in replicationcompromised zebrafish cells.…”

Section: Zygotic Pold1 Becomes More Dispensable Under P53-deficient Cmentioning

confidence: 99%

“…Second, elongation is slowed to allow for the assembly and function of repair machinery. Third, the structure of the stalled replication forks is maintained to prohibit additional damage to the DNA, and finally, the affected cells are prohibited from undergoing mitosis (for reviews see Nyberg et al 8 and Bartek et al 9 ). If replication forks are not repaired and/or stalled for too long, cells either proceed to G2/M arrest 10,11 or undergo apoptosis by the instructions of the tumor suppressor and transcription factor p53 (reviewed in Haupt et al 12 ).…”

Section: Introductionmentioning

confidence: 99%

p53 deficiency rescues apoptosis and differentiation of multiple cell types in zebrafish flathead mutants deficient for zygotic DNA polymerase δ1

et al. 2005

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Cell culture work has identified the tumor suppressor p53 as a component of the S-phase checkpoint control system, while in vivo studies of this role of p53 in whole-vertebrate systems were limited. Here, we describe zebrafish mutants in the DNA polymerase delta catalytic subunit 1, based on the positional cloning of the flathead (fla) gene. fla mutants display specific defects in late proliferative zones, such as eyes, brain and cartilaginous elements of the visceral head skeleton, where cells display compromised DNA replication, followed by apoptosis, and partial or complete loss of affected tissues. Antisense-mediated knockdown of p53 in fla mutants leads to a striking rescue of all phenotypic traits, including completion of replication, survival of cells, and normal differentiation and tissue formation. This indicates that under replicationcompromised conditions, the p53 branch of the S-phase checkpoint is responsible for eliminating stalled cells that, given more time, would have otherwise finished their normal developmental program.

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Toward Maintaining the Genome: DNA Damage and Replication Checkpoints

Cited by 715 publications

References 233 publications

Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53

Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

p53 deficiency rescues apoptosis and differentiation of multiple cell types in zebrafish flathead mutants deficient for zygotic DNA polymerase δ1

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