Exploring and exploiting the systemic effects of deregulated replication licensing

Petrakis, Theodoros G.; Komseli, Eirini-Stavroula; Papaioannou, Marilena D.; Vougas, Konstantinos; Polyzos, A.; Myrianthopoulos, Vassilios; Mikros, Emmanuel; Trougakos, Ioannis P.; Thanos, Dimitris; Branzei, Dana; Townsend, Paul A.; Gorgoulis, Vassilis G.

doi:10.1016/j.semcancer.2015.12.002

Cited by 37 publications

(34 citation statements)

References 129 publications

(159 reference statements)

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“…In line with this notion, we showed that protracted p21 WAF1/Cip1 expression abrogated the property of PCNA to regulate the degradation cycle of the replication licensing factors Cdt1 and Cdc6, 6 triggering re-replication. 5 Consecutively, p21…”

supporting

confidence: 71%

“…The selective process is actually an extensive error-prone repair process that ensures that over time the "fittest and more stable cells" will survive and emerge. 5 An essential biochemical act assisting in p21 WAF1/Cip1 senescence bypass is suppression of the INK4/ARF locus by the deregulated replication licensing factor Cdc6, 6 rendering the senescent phase reversible. 2 Another consequence of continuous p21 WAF1/Cip1 expression, related to PCNA-dependent functions, could be suppression of PCNA mono-ubiquitinilation (data not shown), essential for translesion DNA synthesis (TLS) and repair.…”

mentioning

confidence: 99%

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p21^WAF1/Cip1 - PCNA: Fatal attraction

2016

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confidence: 71%

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confidence: 99%

p21^WAF1/Cip1 - PCNA: Fatal attraction

2016

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“…The HBEC cell line was developed as described in ref. 31. Briefly, immortalized HBECs were infected with PLVX-Tet-On with blasticidin resistance (3 μg/mL) and PLVX-TRE-Cdc6 with zeocin resistance (12.5 μg/mL).…”

Section: Methodsmentioning

confidence: 99%

Unreplicated DNA remaining from unperturbed S phases passes through mitosis for resolution in daughter cells

Moreno

Carrington

Albergante

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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To prevent rereplication of genomic segments, the eukaryotic cell cycle is divided into two nonoverlapping phases. During late mitosis and G1 replication origins are "licensed" by loading MCM2-7 double hexamers and during S phase licensed replication origins activate to initiate bidirectional replication forks. Replication forks can stall irreversibly, and if two converging forks stall with no intervening licensed origin-a "double fork stall" (DFS)-replication cannot be completed by conventional means. We previously showed how the distribution of replication origins in yeasts promotes complete genome replication even in the presence of irreversible fork stalling. This analysis predicts that DFSs are rare in yeasts but highly likely in large mammalian genomes. Here we show that complementary strand synthesis in early mitosis, ultrafine anaphase bridges, and G1-specific p53-binding protein 1 (53BP1) nuclear bodies provide a mechanism for resolving unreplicated DNA at DFSs in human cells. When origin number was experimentally altered, the number of these structures closely agreed with theoretical predictions of DFSs. The 53BP1 is preferentially bound to larger replicons, where the probability of DFSs is higher. Loss of 53BP1 caused hypersensitivity to licensing inhibition when replication origins were removed. These results provide a striking convergence of experimental and theoretical evidence that unreplicated DNA can pass through mitosis for resolution in the following cell cycle.uring the eukaryotic cell cycle, the genome must be precisely duplicated with no sections left unreplicated and no sections replicated more than once. To prevent rereplication, the process is divided into two nonoverlapping phases: during late mitosis and G1 replication origins are "licensed" for subsequent use by loading MCM2-7 double hexamers, and during S phase DNAbound MCM2-7 is activated to form processive CMG (CDC45-MCM-GINS) helicases that drive replication fork progression. The prohibition of origin licensing during S phase and G2 ensures that rereplication of DNA cannot occur. However, the inability to license new origins after the onset of S phase provides a challenge for the cell to fully replicate the genome using its finite supply of licensed origins. Replication forks can irreversibly stall when they encounter unusual structures on the DNA, such as DNA damage or tightly bound protein-DNA complexes.When replication initiation occurs at a licensed replication origin the MCM2-7 double hexamer forms a pair of bidirectionally orientated CMG helicases (1-3). If one fork irreversibly stalls, the converging fork from a neighboring origin can compensate by replicating all of the DNA up to the stalled fork. However, if two converging forks both stall and there is no licensed origin between them-a "double fork stall" (DFS)-new replicative machinery cannot be recruited to replicate the intervening DNA (4). To compensate for this potential for underreplication, origins are licensed redundantly, with most (typically >70%) remaining dorm...

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“…Together with NOTCH1 they can promote EMT by upregulating classical EMT inducers that suppress E-cadherin. Intriguingly, FOXM1 also promotes expression of the replication licensing factor CDC6, which when overexpressed can repress E-cadherin and trigger genomic instability [3, 4]. In a RAS activated background CDC6 mediated E-cadherin suppression results in EMT [4].…”

mentioning

confidence: 99%