The cyclin-dependent kinase inhibitor Dacapo promotes replication licensing during Drosophila endocycles

Hong, Amy; Narbonne-Reveau, Karine; Riesgo-Escovar, Juan R.; Fu, Haiqing; Aladjem, Mirit I.; Lilly, Mary A.

doi:10.1038/sj.emboj.7601648

Cited by 50 publications

(73 citation statements)

References 57 publications

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“…DNA damage in these regions may be the result of replication forks "catching up" with stalled forks from previous endocycle S phases. These observations and model are consistent with a previous report of heterochromatic repair foci in endocycle cells of the ovary (Hong et al 2007). In fact, previous analyses had indicated that these chromatin junctions are fragile in the endocycle, and that fragility correlates with the degree of underreplication (Karpen and Spradling 1990;Leach et al 2000;B.…”

Section: Damage At Chromatin Junctions In Both Normal and Rereplicatisupporting

confidence: 82%

“…Kolpakas, S. Maqbool, and B. Calvi, unpubl.). Moreover, previous evidence suggested that the Dup inhibitor Geminin, and periodic inhibition of CDK2, is important for normal endocycle DNA replication (Hong et al 2007;Narbonne Reveau et al 2008;Zielke et al 2008). It is possible, however, that some aspects of the origin licensing mechanism differ between mitotic cycles and endocycles.…”

Section: Rereplication Is Distinct From the Normal Process Of Endoredmentioning

confidence: 92%

“…Thereafter, they selectively rereplicate only a few loci, resulting in amplification of gene copy number (Calvi et al 1998). Similar to mitotic cycles, MCM proteins periodically associate with chromatin during each endocycle G phase, and Dup protein is proteolyzed at the G/S transition, suggesting that Dup regulation may be important for licensing control of origins in the endocycle (Su and O'Farrell 1998;Whittaker et al 2000;Thomer et al 2004;Hong et al 2007). To test this idea, we used a heat-inducible hsp70:Myc:FL-Dup strain to examine the effect of Dup overexpression on mitotic cycle and endocycling follicle cells.…”

Section: Elevated Dup Protein Induces Rereplication In Mitotic Cyclinmentioning

confidence: 99%

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Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Mehrotra¹,

Maqbool²,

Kolpakas³

et al. 2008

Genes Dev.

127

155

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Initiation of DNA replication at origins more than once per cell cycle results in rereplication and has been implicated in cancer. Here we use Drosophila to examine the checkpoint responses to rereplication in a developmental context. We find that increased Double-parked (Dup), the Drosophila ortholog of Cdt1, results in rereplication and DNA damage. In most cells, this rereplication triggers caspase activation and apoptotic cell death mediated by both p53-dependent and -independent pathways. Elevated Dup also caused DNA damage in endocycling cells, which switch to a G/S cycle during normal development, indicating that rereplication and the endocycling DNA reduplication program are distinct processes. Unexpectedly, however, endocycling cells do not apoptose regardless of tissue type. Our combined evidence suggests that endocycling apoptosis is repressed in part because proapoptotic gene promoters are silenced. Normal endocycling cells had DNA lesions near heterochromatin, which increased after rereplication, explaining why endocycling cells must constantly repress the genotoxic apoptotic response. Our results reveal a novel regulation of apoptosis in development and new insights into the little-understood endocycle. Similar mechanisms may operate during vertebrate development, with implications for cancer predisposition in certain tissues.[Keywords: DNA replication; DNA damage; endocycle; checkpoint; apoptosis] Supplemental material is available at http://www.genesdev.org. The timely duplication of the genome during S phase of every cell division cycle requires that DNA replication initiate from thousands of origins. If too few origins initiate, replication forks can collapse, resulting in DNA damage and incomplete replication of the genome. Initiation of DNA replication from origins more than once per cell cycle, however, results in "rereplication" and subsequent DNA damage (Arias and Walter 2007). In recent years, it has become increasingly apparent that problems with DNA replication are common in premalignant cells, with subsequent checkpoint defects leading to genome instability and cancer (Dutta 2007). It remains unclear, however, whether all cells in development are equivalent with respect to their regulation of DNA replication and checkpoint responses. Here, we use Drosophila to investigate the checkpoint responses to rereplication in a developmental context. Two important steps in the cell cycle regulation of DNA replication are the assembly and activation of a prereplicative complex (pre-RC) (Sivaprasad et al. 2006). The pre-RC assembles onto origins in early G1 and is subsequently activated in S phase. During pre-RC assembly, the hexameric origin recognition complex (ORC) serves as a scaffold for origin association of Cdc6 and Cdt1, which are both required to load the hexameric minichromosome maintenance complex (MCM), the replicative helicase (Randell et al. 2006;Sivaprasad et al. 2006). Once the MCM complex is tightly bound, the origins are considered to be "licensed" and competent to initiate replic...

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Section: Damage At Chromatin Junctions In Both Normal and Rereplicatisupporting

confidence: 82%

Section: Rereplication Is Distinct From the Normal Process Of Endoredmentioning

confidence: 92%

Section: Elevated Dup Protein Induces Rereplication In Mitotic Cyclinmentioning

confidence: 99%

See 1 more Smart Citation

Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Mehrotra¹,

Maqbool²,

Kolpakas³

et al. 2008

Genes Dev.

127

155

View full text Add to dashboard Cite

show abstract

“…This allows Cyclin E/cdk2 to phosphorylate Cdt1/Dup, leading to its degradation. 16 This model also fits well with the observations that fluctuation of CyclinE/ cdk2 activities is required for progression of endocycles 17,18 and that constitutive Cyclin E expression first induces and then inhibits endoreplication. [19][20][21] It appears as if endocycling cells single-mindedly pursue the mission of polyploidy: they eliminate mitosis by shutting down mitotic cyclin activities, 22,23 eliminate cell cycle arrest by shutting down checkpoint pathways to go through multi-round of replication with under-replicated heterochromatin (reviewed in refs.…”

supporting

confidence: 68%

“…[19][20][21] It appears as if endocycling cells single-mindedly pursue the mission of polyploidy: they eliminate mitosis by shutting down mitotic cyclin activities, 22,23 eliminate cell cycle arrest by shutting down checkpoint pathways to go through multi-round of replication with under-replicated heterochromatin (reviewed in refs. 24 and 25), and eliminate regulation by the ORC to trigger initiation 17,27,28 primarily by modifying the activities of Cdc6. In this model, assembly of pre-RC is initiated by recruitment of Cdc6 to Protein X, which is mediated by Cyclin E. Cdc6 then recruits Dup after it is dissociated from Geminin.…”

mentioning

confidence: 99%