Thymine DNA Glycosylase Is a CRL4Cdt2 Substrate

Slenn, Tamara Jeannine; Morris, Benjamin L.; Havens, Courtney G.; Freeman, Robert M.; Takahashi, Tatsuro; Walter, Johannes C.

doi:10.1074/jbc.m114.574194

Cited by 44 publications

(53 citation statements)

References 65 publications

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“…Importantly, however, CDT2 chromatin recruitment could conceivably be achieved by any PIP degron-PCNA complex in sufficient abundance; we infer that not only is the interaction between CDT2 and the substrates tested here inhibited, but the interaction between CDT2 and any as yet undiscovered substrates is also inhibited. For example, two recent reports identified thymine DNA glycosylase as a target of CRL4 CDT2 in Xenopus and human cells (6,7). The behavior of our two reporter substrates and accumulated findings herein suggest that thymine DNA glycosylase is also protected via CDK1.…”

Section: Pled Destruction Via Crl4mentioning

confidence: 63%

“…Among the cohort of human proteins reported to be subject to replication-coupled destruction are CDT1, SET8, p12, the CDK inhibitor p21, and, most recently, thymine DNA glycosylase (6,7). Their destruction in S phase is particularly critical to ensure precise and efficient genome duplication (1)(2)(3)(4)(5)(6)(7).…”

mentioning

confidence: 99%

“…Their destruction in S phase is particularly critical to ensure precise and efficient genome duplication (1)(2)(3)(4)(5)(6)(7). CDT1 is required in G 1 for rendering DNA replication origins competent for initiation in S phase (a process termed "origin licensing") (8,9).…”

mentioning

confidence: 99%

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CDK1-dependent Inhibition of the E3 Ubiquitin Ligase CRL4CDT2 Ensures Robust Transition from S Phase to Mitosis

Rizzardi¹,

Coleman²,

Varma

et al. 2015

Journal of Biological Chemistry

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Background: CRL4CDT2 mediates replication-coupled destruction during S phase. CRL4 CDT2 substrates reaccumulate by an unexplored mechanism. Results: CDK1 activity blocks CRL4CDT2 by preventing chromatin recruitment of the substrate receptor, CDT2. Conclusion: CDK1 activity facilitates CRL4 CDT2 substrate reaccumulation upon S phase exit; several of these substrates are then required for normal mitotic progression. Significance: We provide the first evidence that CDK1 regulates the activity of CRL4 CDT2 .

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Section: Pled Destruction Via Crl4mentioning

confidence: 63%

mentioning

confidence: 99%

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CDK1-dependent Inhibition of the E3 Ubiquitin Ligase CRL4CDT2 Ensures Robust Transition from S Phase to Mitosis

Rizzardi¹,

Coleman²,

Varma

et al. 2015

Journal of Biological Chemistry

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“…This process is promoted by the E3 ubiquitin ligase complex Cul4-DDB1-RBX1 in association with Cdt2 (cumulatively named "CRL4 Cdt2 ") and is dependent on the interaction of TDG with PCNA (32,33). The site of ubiquitylation within TDG was not identified, and the influence of other PTMs (i.e., acetylation, phosphorylation, and SUMOylation) on the degradation process is currently unknown.…”

Section: Figmentioning

confidence: 99%

Base Excision Repair, a Pathway Regulated by Posttranslational Modifications

Carter

Parsons

2016

Molecular and Cellular Biology

129

105

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Base excision repair (BER) is an essential DNA repair pathway involved in the maintenance of genome stability and thus in the prevention of human diseases, such as premature aging, neurodegenerative diseases, and cancer. Protein posttranslational modifications (PTMs), including acetylation, methylation, phosphorylation, SUMOylation, and ubiquitylation, have emerged as important contributors in controlling cellular BER protein levels, enzymatic activities, protein-protein interactions, and protein cellular localization. These PTMs therefore play key roles in regulating the BER pathway and are consequently crucial for coordinating an efficient cellular DNA damage response. In this review, we summarize the presently available data on characterized PTMs of key BER proteins, the functional consequences of these modifications at the protein level, and also the impact on BER in vitro and in vivo. It has been estimated that every day, each human cell generates Ͼ10,000 DNA base lesions as a consequence of the instability of DNA, caused by hydrolysis, cellular oxidative metabolism, and environmental factors, including ionizing radiation (IR) (1). Such sites of DNA base damage include base loss (apurinic/apyrimidinic [AP] sites), DNA base modifications (e.g., base alkylation and oxidation), and DNA single-strand breaks (SSBs), which are a major threat to the integrity of the human genome. In the 1970s, Tomas Lindahl (corecipient of the 2015 Nobel Prize in chemistry) was the first to identify a DNA N-glycosylase, namely, uracil DNA N-glycosylase (UNG), that excises uracil residues from DNA (2). Lindahl recognized that following UNG activity, an endonuclease, a DNA polymerase (Pol), and a DNA ligase (Lig) would be required to complete the "excision-repair" process, and this formed the starting point for the identification of the base excision repair (BER) pathway. Since then, most of the major enzymes involved in BER have been identified and characterized in terms of their roles and enzymatic activities.BER is a coordinated process ( Fig. 1) and in humans is initiated by 1 of 11 damage-specific DNA glycosylases. These enzymes display substrate specificity for particular types of damaged DNA bases and employ a "base-flipping" mechanism to excise these DNA lesions (3, 4). There are two different types of DNA glycosylases, monofunctional glycosylases (DNA glycosylase activity only) and bifunctional glycosylases (DNA glycosylase plus DNA strand cleavage activities). Monofunctional DNA glycosylases sever the N-glycosidic bond between the damaged base and the phosphodiester DNA backbone, creating an AP site. The AP site is recognized by AP endonuclease 1 (APE1), which cleaves the DNA backbone, resulting in the formation of a one nucleotide gap flanked by 3=-hydroxyl and 5=-deoxyribosephosphate (5=-dRP) ends (5, 6). Conversely, bifunctional DNA glycosylases, in addition to performing base damage removal, incise the DNA backbone to create a single-nucleotide gap flanked by either a 5= phosphate and a 3=-␣,␤-unsaturated aldehyde (ter...

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“…[11][12][13] The p21, Set8, and thymine DNA glycosylase proteins are degraded by the same pathway as Cdt1. [14][15][16][17][18][19][20][21] Analyses of target proteins led to the identification of a common sequence, called the PIP-degron, which comprises a canonical PIP box and conserved amino acids within and downstream of the PIP box;…”

Section: Crl4mentioning

confidence: 99%

Mismatch repair proteins recruited to ultraviolet light-damaged sites lead to degradation of licensing factor Cdt1 in the G1 phase

et al. 2017

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Cdt1 is rapidly degraded by CRL4Cdt2 E3 ubiquitin ligase after UV (UV) irradiation. Previous reports revealed that the nucleotide excision repair (NER) pathway is responsible for the rapid Cdt1-proteolysis. Here, we show that mismatch repair (MMR) proteins are also involved in the degradation of Cdt1 after UV irradiation in the G1 phase. First, compared with the rapid (within »15 min) degradation of Cdt1 in normal fibroblasts, Cdt1 remained stable for »30 min in NER-deficient XP-A cells, but was degraded within »60 min. The delayed degradation was also dependent on PCNA and CRL4 Cdt2. The MMR proteins Msh2 and Msh6 were recruited to the UV-damaged sites of XP-A cells in the G1 phase. Depletion of these factors with small interfering RNAs prevented Cdt1 degradation in XP-A cells. Similar to the findings in XP-A cells, depletion of XPA delayed Cdt1 degradation in normal fibroblasts and U2OS cells, and co-depletion of Msh6 further prevented Cdt1 degradation. Furthermore, depletion of Msh6 alone delayed Cdt1 degradation in both cell types. When Cdt1 degradation was attenuated by high Cdt1 expression, repair synthesis at the damaged sites was inhibited. Our findings demonstrate that UV irradiation induces multiple repair pathways that activate CRL4Cdt2 to degrade its target proteins in the G1 phase of the cell cycle, leading to efficient repair of DNA damage.

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Thymine DNA Glycosylase Is a CRL4Cdt2 Substrate

Cited by 44 publications

References 65 publications

CDK1-dependent Inhibition of the E3 Ubiquitin Ligase CRL4CDT2 Ensures Robust Transition from S Phase to Mitosis

CDK1-dependent Inhibition of the E3 Ubiquitin Ligase CRL4CDT2 Ensures Robust Transition from S Phase to Mitosis

Base Excision Repair, a Pathway Regulated by Posttranslational Modifications

Mismatch repair proteins recruited to ultraviolet light-damaged sites lead to degradation of licensing factor Cdt1 in the G1 phase

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