A DNA-binding domain in the C-terminal region of Cdt2 enhances the DNA synthesis-coupled CRL4Cdt2 ubiquitin ligase activity for Cdt1

Mazian, Muadz Ahmad; Suenaga, Naohiro; Ishii, Takashi; Hayashi, Akiyo; Shiomi, Yuki; Nishitani, Hideo

doi:10.1093/jb/mvz001

Cited by 4 publications

(15 citation statements)

References 50 publications

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“…Similar to animal Cdt1 that requires a SCF Skp2 complex, Arabidopsis CDT1a is targeted for degradation by a SCF FBL17 complex, a process that likely requires CDK activity (Castellano et al, 2004). The other pathway that controls human Cdt1 level is mediated by the Cdt2 protein, which is part of a CRL4 complex and instead of phosphorylation, requires interaction of Cdt1 with PCNA (Hayashi et al, 2018;Mazian et al, 2019;Nishitani et al, 2006). This Cdt1 targeting mechanism is mediated by a PCNAinteracting protein (PIP) motif located at the N-terminus of human Cdt1 (Havens and Walter, 2011), which is not conserved in all animal species.…”

Section: Discussionmentioning

confidence: 99%

FBL17 targets CDT1a for degradation in early S-phase to prevent Arabidopsis genome instability

Desvoyes

Noir

Masoud

et al. 2019

Preprint

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Maintenance of genome integrity depends on controlling the availability of DNA replication initiation proteins, e.g., CDT1, a component of the pre-replication complexes that regulates chromatin licensing for replication. To understand the evolutionary history of CDT1 regulation, we have identified the mechanisms involved in CDT1 dynamics. During cell cycle, CDT1a starts to be loaded early after mitotic exit and maintains high levels until the G1/S transition. Soon after the S-phase onset, CDT1a is rapidly degraded in a proteasomedependent manner. Plant cells use a specific SCF-mediated pathway that relies on the FBL17 F-box protein for CDT1a degradation, which is independent of CUL4a-containing complexes. A similar oscillatory pattern occurs in endoreplicating cells, where CDT1a is loaded just after finishing the S-phase. CDT1a is necessary to maintain genome stability, an ancient strategy although unique proteins and mechanisms have evolved in different eukaryotic lineages to ensure its degradation during S-phase.

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Section: Discussionmentioning

confidence: 99%

FBL17 targets CDT1a for degradation in early S-phase to prevent Arabidopsis genome instability

Desvoyes

Noir

Masoud

et al. 2019

Preprint

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“…Cdt2, also known as DCAF2 and DCX (DTL) [ 13 , 17 ], is one of the 90 DCAFs, substrate receptors associated with CRL4 ubiquitin ligase [ 7 ]. In contrast to Cdt2 from fission yeast, which mainly consists of WD40 repeats, Cdt2 proteins from higher eukaryotes contain more than 700 aa and have extended C-terminal regions ( Figure 1 B) [ 18 , 19 ]. However, the effect of the length of the Cdt2 C-terminus on CRL4 ligase activity remains unclear.…”

Section: Cdt2- Ddb1-cul4-rbx1 Complex Crl4 Cdt2mentioning

confidence: 99%

“…Although the simulation suggested that the Cdt2 N-terminal region alone was sufficient for recruitment to PIP-degron-bound PCNA DNA , UV-induced DNA damage showed that the Cdt2 N-terminal region (residues 1–417) alone was not recruited to this site [ 33 ]. The failed recruitment of Cdt2 resulted in the stabilization of the critical substrates Cdt1, Set8 and p21, which are prone to cause DNA re-replication [ 19 , 34 , 35 ]. Thus, the C-terminal of Cdt2 is required for this molecule to have a full ubiquitin ligase activity.…”

Section: Substrate Recognition By the N-terminal Region Of Cdt2mentioning

confidence: 99%

“…The less conserved C-terminus of Cdt2 is associated with the intrinsically disordered region (IDR) of this molecule, with the pattern of the disordered region conserved in Cdt2 proteins from humans, mice, chickens, zebrafish, and Xenopus ( Figure 1 C). Furthermore, this IDR has been shown to play a crucial role in regulating Cdt2 activity [ 19 , 33 , 36 ]. Our group has successfully identified the essential features present in the C-terminus of Cdt2 that regulate Cdt2 activity [ 19 , 33 , 36 ].…”

Section: Essential Features In the C-terminus Of Cdt2 That Regulate C...mentioning

confidence: 99%

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CRL4Cdt2 Ubiquitin Ligase, A Genome Caretaker Controlled by Cdt2 Binding to PCNA and DNA

Mazian

Yamanishi

Rahman

et al. 2022

Genes

Self Cite

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The ubiquitin ligase CRL4Cdt2 plays a vital role in preserving genomic integrity by regulating essential proteins during S phase and after DNA damage. Deregulation of CRL4Cdt2 during the cell cycle can cause DNA re-replication, which correlates with malignant transformation and tumor growth. CRL4Cdt2 regulates a broad spectrum of cell cycle substrates for ubiquitination and proteolysis, including Cdc10-dependent transcript 1 or Chromatin licensing and DNA replication factor 1 (Cdt1), histone H4K20 mono-methyltransferase (Set8) and cyclin-dependent kinase inhibitor 1 (p21), which regulate DNA replication. However, the mechanism it operates via its substrate receptor, Cdc10-dependent transcript 2 (Cdt2), is not fully understood. This review describes the essential features of the N-terminal and C-terminal parts of Cdt2 that regulate CRL4 ubiquitination activity, including the substrate recognition domain, intrinsically disordered region (IDR), phosphorylation sites, the PCNA-interacting protein-box (PIP) box motif and the DNA binding domain. Drugs targeting these specific domains of Cdt2 could have potential for the treatment of cancer.

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“…The largest drop in p21 levels occurs in early S phase and is dependent on the CRL4 CDT2 E3 ubiquitin ligase. Targeting by CRL4 CDT2 requires recruitment of both the E3 ubiquitin ligase and the p21 substrate to DNA‐loaded PCNA at replication forks in a process termed replication‐coupled destruction . The precise dynamics of CDK inhibitor degradation is a combination of the rate of ubiquitylation and the action of deubiquitinases that oppose ubiquitylation .…”

Section: S Phase Entrymentioning

confidence: 99%

Preparation for DNA replication: the key to a successful S phase

Limas

Cook

2019

FEBS Letters

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Successful genome duplication is required for cell proliferation and demands extraordinary precision and accuracy. The mechanisms by which cells enter, progress through, and exit S phase are intense areas of focus in the cell cycle and genome stability fields. Key molecular events in the G1 phase of the cell division cycle, especially origin licensing, are essential for pre‐establishing conditions for efficient DNA replication during the subsequent S phase. If G1 events are poorly regulated or disordered, then DNA replication can be compromised leading to genome instability, a hallmark of tumorigenesis. Upon entry into S phase, coordinated origin firing and replication progression ensure complete, timely, and precise chromosome replication. Both G1 and S phase progressions are controlled by master cell cycle protein kinases and ubiquitin ligases that govern the activity and abundance of DNA replication factors. In this short review, we describe current understanding and recent developments related to G1 progression and S phase entrance and exit with a particular focus on origin licensing regulation in vertebrates.

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A DNA-binding domain in the C-terminal region of Cdt2 enhances the DNA synthesis-coupled CRL4Cdt2 ubiquitin ligase activity for Cdt1

Cited by 4 publications

References 50 publications

FBL17 targets CDT1a for degradation in early S-phase to prevent Arabidopsis genome instability

FBL17 targets CDT1a for degradation in early S-phase to prevent Arabidopsis genome instability

CRL4Cdt2 Ubiquitin Ligase, A Genome Caretaker Controlled by Cdt2 Binding to PCNA and DNA

Preparation for DNA replication: the key to a successful S phase

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