Review ArticleReviewsR

The Licensing Factor Cdt1 Links Cell Cycle Progression to the DNA Damage Response

ALEXANDRA KANELLOU, NICKOLAOS NIKIFOROS GIAKOUMAKIS, ANDREAS PANAGOPOULOS, SPYRIDON CHAMPERIS TSANIRAS and ZOI LYGEROU
Anticancer Research May 2020, 40 (5) 2449-2456; DOI: https://doi.org/10.21873/anticanres.14214

Abstract

The maintenance of genome integrity is essential for cellular survival and propagation. It relies upon the accurate and timely replication of the genetic material, as well as the rapid sensing and repairing of damage to DNA. Uncontrolled DNA replication and unresolved DNA lesions contribute to genomic instability and can lead to cancer. Chromatin licensing and DNA replication factor 1 (Cdt1) is essential for loading the minichromosome maintenance 2-7 helicase complex onto chromatin exclusively during the G1 phase of the cell cycle, thus limiting DNA replication to once per cell cycle. Upon DNA damage, Cdt1 rapidly accumulates to sites of damage and is subsequently poly-ubiquitinated by the cullin 4-RING E3 ubiquitin ligase complex, in conjunction with the substrate recognition factor Cdt2 (CRL4Cdt2), and targeted for degradation. We here discuss the cellular functions of Cdt1 and how it may interlink cell cycle regulation and DNA damage response pathways, contributing to genome stability.

During every cell division, cells must ensure that they pass down a full and accurate copy of their genetic material to their daughter cells. To achieve this, all eukaryotic cells carry out a strict series of events, known as the cell cycle, which permits genomic DNA to be copied once and only once during the S phase of the cell cycle, before one copy of each chromosome is passed down to the daughter cells during mitosis (1, 2). Multiple protein complexes associate with chromatin throughout the cell cycle to coordinate cell cycle events and ensure timely DNA replication and chromosome segregation (1, 2). In addition, mistakes made during DNA replication or damage to DNA brought about by endogenous or exogenous factors must be quickly sensed and repaired. For this reason, hundreds of cellular proteins constantly scan the DNA to recognize damaged sites and recruit additional protein complexes to orchestrate repair and signal to the cell cycle machinery the presence of damage and, therefore, the need to halt further cell cycle progression. This DNA damage response (DDR) must be closely coordinated with the cell cycle machinery to ensure the maintenance of genomic stability. Factors linking the DDR to the cell cycle have attracted significant attention in recent years (3-6), while defects in this coordination can lead to genomic instability and are closely linked to disease, most prominently to cancer (7, 8).

In this review, we focus on the chromatin licensing and DNA replication factor 1 (Cdt1), a cell cycle regulator essential for timely DNA replication. We discuss the cellular function of Cdt1, as well as its link with the pathways that sense and repair DNA damage. Moreover, we describe how this link could affect both cell cycle progression and cellular DNA damage response. Experimental data from our group (Figures 1, 2 and 3) are used to illustrate key points, consistent with earlier findings.

Cdt1 Is a Central Regulator of DNA Replication Licensing

Cdt1 was originally identified in fission yeast as a gene regulated by the cell cycle transcription factor Cdc10, and was named Cdc10-dependent transcript 1 (9). It was shown to be important both for entry into S phase and for arresting progression to mitosis in the absence of DNA replication (9). Functional characterization of Cdt1 showed it to be required for the loading of minichromosome maintenance (MCM) proteins onto DNA during the G1 phase of the cell cycle in fission yeast (10) and Xenopus egg extracts (11). Cdt1 was also shown to enhance aberrant over-replication brought about by ectopic expression of the licensing factor Cdc18 in fission yeast (10-14). Subsequently, it was revealed that its function was conserved in all eukaryotes (15) and Cdt1 was accordingly renamed to chromatin licensing and DNA replication factor 1.

In the normal cell cycle, DNA is licensed for a new round of DNA replication after passage through mitosis, through the association of the six-subunit MCM complex (MCM2-7) onto DNA replication origins (16, 17). Cdt1 and Cdc6 (Cdc18 in fission yeast) are essential for MCM loading, and therefore for DNA replication licensing. In mammalian cells, replication origins begin to be licensed in telophase, while the majority is licensed in late G1, prior to S phase onset (16, 18, 19). The MCM complex is activated as a helicase when cells enter S phase, and moves ahead of the replication fork, unwinding DNA for replication. Origins that have already fired are not able to fire again within the same cell cycle, as licensing in inhibited and the MCM complex cannot load onto chromatin from S phase until completion of mitosis. Thus, restriction of MCM complex loading exclusively in the G1 phase is pivotal for the maintenance of genome integrity, and is ensured by the tight regulation of the loading factors Cdt1 and Cdc6.

Cdt1 is tightly regulated so as to be present within the nucleus only during the G1 phase of the cell cycle. In Figure 1, it is shown that in cultured human breast cancer cells Cdt1 is detected only in cells that are in G1, consistent with earlier work (20-22). This strict regulation of Cdt1 levels is evident in different tissues (23) and different species (15). Cdt1 protein levels are controlled through cell cycle-specific proteolysis. More specifically, following S phase entry, Cdt1 is poly-ubiquitinated and targeted for proteasome-dependent proteolysis by two major E3 ubiquitin ligases, a Skp1-Cullin-F-box protein complex containing Skp2 (SCFSkp2) and cullin ring ligase CRL4Cdt2 (15, 21). Aberrations in this control bring about untimely licensing and origin refiring within the same cell cycle (15). It has been demonstrated that Cdt1 is misregulated in tumors (24-26), and this misregulation already occurs in early, precancerous lesions (27), while aberrant regulation of Cdt1 leads to dysplasia and malignancy in mice (28-30). Cdt1 is therefore believed to be an important contributor to genomic instability during tumor initiation and progression (8, 31, 32).

Cdt1 Is Proteolysed Following DNA Damage by the Cullin 4-RING E3 Ubiquitin Ligase CRL4Cdt2

Cdt1 has been shown to link cell cycle regulation with the DNA damage response, as it is rapidly proteolyzed when cells experience damage in G1 (33), due to irradiation (33, 34), or drugs (35). As shown in Figure 2, Cdt1 levels drop when MCF-7 breast cancer cells are exposed to ultraviolet irradiation. This DNA damage-dependent proteolysis of Cdt1 is mediated by the CRL4Cdt2 ubiquitin ligase (21, 36), which binds to proliferating cell nuclear antigen (PCNA) loaded onto damaged chromatin. Independent recruitment of Cdt1 and Cdt2 onto DNA-bound PCNA was recently shown to be required for the recognition of Cdt1 by CRL4Cdt2, both after DNA damage and in S phase (37-39), ensuring that Cdt1 poly-ubiquitination takes place only on damaged or replicating DNA. Multiple DNA repair pathways bring about PCNA loading and Cdt1 proteolysis, including the xeroderma pigmentosum pathway and the mismatch repair pathway following UV-irradiation (36, 40, 41), or the cellular response to double-strand breaks.

Cdt1 proteolysis following DNA damage has been suggested as a checkpoint, which inhibits entry into S phase, to ensure time for repair prior to the initiation of DNA replication. Indeed, Cdt1 depletion leads to decreased licensing, while mammalian cells have been shown to possess a checkpoint, which inhibits entry into S phase with incomplete licensing (42-46). This checkpoint is dependent on p53 (44). However, in cancer cells as well as in cells entering the cell cycle from G0 (47, 48), this checkpoint is dysfunctional contributing to the appearance of replication stress (8). Cdt1 proteolysis following DNA damage has also been suggested as a means to inhibit re-replication in damaged cells, where the checkpoints elicited as a response to the presence of damage culminate in the inhibition of cyclin-dependent kinases (CDKs), thus alleviating CDK-mediated blocks to re-replication (49).

Cdt1 Rapidly Accumulates at Sites of DNA Damage

Cdt1 accumulates on damaged chromatin prior to its proteolysis. By using a pulsed laser to induce DNA damage at a specific subnuclear volume in living cells, Cdt1 was shown to be rapidly recruited to the site of DNA lesion, within minutes of the induction of damage (50). This is also evident when cells are locally irradiated with UV, through the use of micropore filters with defined pores (37, 51). As shown in Figure 3, following laser micro-irradiation of MCF7 breast cancer cells, Cdt1 accumulates at sites of damage, marked by the phosphorylated histone variant H2AX (γH2AX).

PCNA and the PCNA interacting protein (PIP) box at the N-terminus of Cdt1 are required for this recruitment, consistent with Cdt1 accumulation taking place through binding to chromatin loaded PCNA (50, 51). Using fluorescence recovery after photobleaching (FRAP) (52-54), Cdt1 was shown to exhibit dynamic binding to sites of damage (37, 50, 55), in contrast to PCNA, which maintains stable interactions with damaged chromatin. The accumulation of Cdt1 to sites of damage is followed by its proteolysis, which is usually completed within 30 min to 2 h, depending on the cell type (37, 50). Therefore, Cdt1 remains associated on damaged DNA for an appreciable time prior to its proteolysis.

Figure 1.
Figure 1.

Cdt1 marks the G1 phase of the cell cycle. MCF7 breast cancer cells were cultured and incubated with the thymidine analogue EdU, which is incorporated in the newly replicated DNA and marks cells in S-phase, for 10 min prior to fixation. Immunofluorescence was performed with specific antibodies against Cdt1 and Cyclin A, which is used as a marker of cells in S and G2 phases of the cell cycle. Cdt1 was detected specifically in the nuclei of cells which are negative for EdU and Cyclin A, and are therefore in the G1 phase of the cell cycle. Nucleolar localization of Cdt1 is also evident. EdU was detected with the use of Click-iT™ EdU Imaging kit (Invitrogen, Thermo Fischer Scientific). Nuclei were stained with DAPI. Images were obtained with a Leica SP5 Confocal microscope. Scale bar: 10 μm.

Figure 2.
Figure 2.

Cdt1 is degraded following ultraviolet (UV)-C irradiation. MCF7 breast cancer cells in culture were irradiated with a UV-C lamp at 10 J/m2 and collected at 60 and 150 min following irradiation. The cells were fixed and immunofluorescence was performed with a specific antibody against Cdt1 and γH2AX. Nuclei were stained with DAPI. Images were obtained with a Leica SP5 Confocal microscope. Scale bar: 10 μm.

Figure 3.
Figure 3.

Cdt1 accumulates at sites of DNA damage. Laser micro-irradiation was performed in MCF7 breast cancer cells seeded in 35 mm imaging dishes (μ-Dish, ibidi, GmbH) with the use of ultraviolet (UV)-A pulsed laser (355 nm) mounted on an IX83 inverted Olympus microscope. The cells were fixed 10 min following irradiation and immunofluorescence was performed with a specific antibody against Cdt1 and γH2AX. Nuclei were stained with Hoechst. Scale bar: 10 μm.

Cdt1 Recruitment to Damaged DNA May Be Important for the DDR

The rapid recruitment of Cdt1 to sites of DNA damage prior to its proteolysis brings about the question of the role of Cdt1 at sites of damage. The cell cycle-specific expression of Cdt1, together with its known properties and interactions, suggest different, non-mutually exclusive, scenarios.

Cdt1 is specifically expressed during the G1 phase of the cell cycle, and its recruitment to sites of damage could signal to the cell the phase of the cell cycle to ensure selection of the appropriate repair pathway. Indeed, different repair pathways must be selected at different cell cycle phases, the most notable being the pathway to repair double-strand breaks. Double-strand breaks are preferentially repaired by non-homologous-end-joining (NHEJ) during the G1 phase, when no sister chromatid is present (4). This pathway is however likely to introduce mutations and the alternative homologous recombination directed repair pathway (HDR) is the pathway of choice following entry into S phase, when a sister chromatid can direct error-free repair (4). Different factors have been shown to ensure the correct choice of double-strand break repair pathway during the cell cycle. Notably, a cyclin-dependent kinase (CDK)-mediated pathway employs the protein CtIP to enhance HDR when CDK levels are increased after the G1 to S phase transition (4). A second pathway was recently described, which uses a histone mark to promote homologous recombination only on newly synthesized chromatin. Specifically, histone H4 unmethylated at lysine 20 (H4K20me0), which marks post-replicative chromatin (56), is recognized by and recruits BRCA1/BARD1, thus directing homologous recombination only to replicated DNA (57). Similarly, the dimethylated H4K20me2 on unreplicated DNA mediates the recruitment of the NHEJ pathway (58, 59). Of note, the methyltransferase that monomethylates H4K20, Set8, is also implicated in licensing (60). Set8 is recruited to sites of DNA damage and proteolyzed through the same pathway as Cdt1 (39, 61-63). Moreover, Set8 is required at sites of damage for the recruitment of the NHEJ factor 53BP1 (64, 65). It is intriguing to speculate that the presence of Cdt1 at sites of damage could signal to the cell the phase of the cell cycle and/or could influence the recruitment and degradation of other CRL4Cdt2 targets, such as Set8.

A function for Cdt1 in fine-tuning recruitment of repair factors to damaged sites has been suggested for trans-lesion synthesis (TLS). Cdt1 recruitment to damaged DNA was shown to inhibit the accumulation of the TLS DNA polymerases eta (Pol η) and kappa (Pol κ) (66). This is brought about by the efficient binding of the PIP degron-containing Cdt1 to PCNA loaded on DNA, which competes with the binding of the PIP motif of polymerases eta and kappa. Thus, recruitment of Pol η and Pol κ to sites of damage, and therefore switch to the error-prone TLS, would only be possible following Cdt1 proteolysis. It should be noted that the rate of CRL4Cdt2-mediated Cdt1 proteolysis is regulated by multiple post-translational modifications, such as Cdt1 and Cdt2 phosphorylation (15, 39) as well as Cdt1 acetylation (67), providing a means of fine-tuning repair.

In addition, Cdt1 recruitment could directly modify chromatin. Cdt1 directly interacts with HBO1, a histone acetylase (68) and the deacetylase HDAC11 (67). Furthermore, Cdt1 binds to Geminin (30) and recruits it onto chromatin (22), while Geminin has been shown to interact with multiple chromatin modifying and remodeling complexes (69, 70). It is conceivable that Cdt1 recruitment to sites of damage could influence the chromatin state, in order to facilitate repair.

Cdt1 was recently shown to contain intrinsically disordered regions at its N-terminus, which possess the ability to lead to liquid-liquid phase separation when mixed with DNA (71). The N-terminus of Cdt1 was previously shown to be required for chromatin association during the G1 phase in living cells (22). Liquid-liquid phase separation, which drives the formation of biomolecular condensates within cells, has attracted significant attention in recent years as a means of subcellular compartmentalization mediating various cellular processes (72). Both DNA replication and DNA repair are organized in supramolecular assemblies within the nucleus, called factories and foci respectively. 53BP1, a key upstream factor for NHEJ, was recently shown to exhibit phase separation properties during DNA repair (73, 74). It could be hypothesized that the physical properties of Cdt1 recruited to sites of damage may affect macromolecular assemblies on damaged chromatin through phase separation, a concept that merits further investigation.

Conclusion

Cdt1, a central cell cycle regulator, ensures that replication occurs once per cell cycle and links the cell cycle to DNA damage responses. This link is likely to affect cell cycle progression in the presence of damage, as Cdt1 degradation inhibits licensing and entry into S phase in cells with an active licensing checkpoint. It may also affect DNA damage responses, by signaling the cell cycle phase, modifying chromatin or fine-tuning the recruitment of different factors to sites of DNA damage. Of note, Cdt1 over-activation directly leads to DNA damage through re-replication (75), while accurate licensing regulation is essential for avoiding replication stress and tumorigenesis (8). In addition to its role in DNA replication licensing and DNA damage responses, Cdt1 is also important for the correct execution of mitosis, being implicated in kinetochore attachment (76, 77), thereby linking DNA replication and repair to chromosome segregation. The observation that Cdt1 is often misregulated in cancer (8, 24-27, 31, 32, 78) underscores the importance of understanding the Cdt1-mediated molecular pathways elicited in damaged cells.

Acknowledgements

The Authors thank the Advanced Light Microscopy Facility of the University of Patras for assistance with microscopy and members of the Lygerou and Taraviras laboratories for fruitful discussions.

Footnotes

  • Authors' Contributions

    All Authors contributed to writing and proofreading the manuscript. AK and NNG performed the experiments shown in figures (AK figure 1, NNG figures 2 and 3) and prepared figures. AP surveyed the literature.

  • This article is freely accessible online.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest.

  • Funding

    This project has been co-financed by the Operational Program “Human Resources Development, Education and Lifelong Learning” and is co-financed by the European Union (European Social Fund) and Greek national funds.

  • Received March 1, 2020.
  • Revision received April 6, 2020.
  • Accepted April 14, 2020.

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The Licensing Factor Cdt1 Links Cell Cycle Progression to the DNA Damage Response
ALEXANDRA KANELLOU, NICKOLAOS NIKIFOROS GIAKOUMAKIS, ANDREAS PANAGOPOULOS, SPYRIDON CHAMPERIS TSANIRAS, ZOI LYGEROU
Anticancer Research May 2020, 40 (5) 2449-2456; DOI: 10.21873/anticanres.14214
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