Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation

Henneke, Ghislaine; Koundrioukoff, Stéphane; Hübscher, Ulrich

doi:10.1038/sj.onc.1206606

Cited by 101 publications

(93 citation statements)

References 57 publications

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“…Fen1 functionally and physically interacts with pol ß to promote strand displacement and flap hydrolysis [11,120]. The functionality of Fen1 is further modified by phosphorylation [121] and acetylation [122,123], each modification providing a different level of regulation. Whereas phosphorylation prevents Fen1-mediated stimulation of PCNA, acetylation by p300 appears to reduce the ability of Fen1 to bind to DNA and to function as a nuclease, with no effect on its PCNA interaction (Table III).…”

Section: Post-translational Modifications Of Ber Gap Tailoring Proteinsmentioning

confidence: 99%

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Almeida¹,

Sobol²

2007

DNA Repair

378

374

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Base excision repair (BER) proteins act upon a significantly broad spectrum of DNA lesions that result from endogenous and exogenous sources. Multiple sub-pathways of BER (short-path or longpatch) and newly designated DNA repair pathways (e.g., SSBR and NIR) that utilize BER proteins complicate any comprehensive understanding of BER and its role in genome maintenance, chemotherapeutic response, neurodegeneration, cancer or aging. Herein, we propose a unified model of BER, comprised of three functional processes: Lesion Recognition/Strand Scission, Gap Tailoring and DNA Synthesis/Ligation, each represented by one or more multiprotein complexes and coordinated via the XRCC1/DNA Ligase III and PARP1 scaffold proteins. BER therefore may be represented by a series of repair complexes that assemble at the site of the DNA lesion and mediates repair in a coordinated fashion involving protein-protein interactions that dictate subsequent steps or sub-pathway choice. Complex formation is influenced by post-translational protein modifications that arise from the cellular state or the DNA damage response, providing an increase in specificity and efficiency to the BER pathway. In this review, we have summarized the reported BER proteinprotein interactions and protein post-translational modifications and discuss the impact on DNA repair capacity and complex formation.

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Section: Post-translational Modifications Of Ber Gap Tailoring Proteinsmentioning

confidence: 99%

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Almeida¹,

Sobol²

2007

DNA Repair

378

374

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“…FEN1 is involved in the processing of Okazaki fragments during DNA replication in S phase, and is phosphorylated by cyclin A-dependent kinases, which are only active at this specific stage of the cell cycle [46]. Although lacking a regular PDSM motif, the three-dimensional structure of the protein reveals that a phosphorylated serine residue lies adjacent to the SUMO acceptor site [47].…”

Section: Sumoylation and Cyclin-dependent Kinases In Concertmentioning

confidence: 99%

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Eifler

Vertegaal

2015

Trends in Biochemical Sciences

234

211

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SUMOylation plays critical roles during cell cycle progression. Many important cell cycle regulators, including many oncogenes and tumor suppressors, are functionally regulated via SUMOylation. The dynamic SUMOylation pattern observed throughout the cell cycle is ensured via distinct spatial and temporal regulation of the SUMO machinery. Additionally, SUMOylation cooperates with other post-translational modifications to mediate cell cycle progression. Deregulation of these SUMOylation and deSUMOylation enzymes causes severe defects in cell proliferation and genome stability. Different types of cancers were recently shown to be dependent on a functioning SUMOylation system, a finding that could potentially be exploited in anti-cancer therapies. KeywordsSUMO; mitosis; SUMOylation; cancer; cell cycle SUMO: a ubiquitin-like modifier that regulates nuclear processesThe complexity of eukaryotic proteomes is widely expanded by protein processing and a vast array of posttranslational modifications. The quick and reversible attachment of small modifiers is essential for all cellular processes and ensures dynamic and rapid responses to extracellular and intracellular stimuli. Apart from chemical modifications such as phosphorylation [1], glycosylation [2] and acetylation [3], small polypeptides can be attached to proteins, resulting in a change in the activity, localization, half-life or interactome of the target protein. Since the initial discovery of ubiquitin, the founding member of these small protein posttranslational modifications in 1975 [4], a large family of structurally related ubiquitin-like modifiers has been uncovered including SUMO, Nedd8, ISG15, FAT10, FUB1, UFM1, URM1, Atg12 and Atg8 [5][6][7][8]. The attachment of these small ubiquitin-like modifiers is catalysed by an enzymatic cascade consisting of an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3), and can be reversed by specific and cell cycle control. It is therefore not surprising that SUMO signal transduction has been implicated in the development of several different cancer types, which could potentially be exploited in anti-cancer therapies. In this review we will focus on the role of SUMO in cell cycle regulation, specifically highlighting its physiological relevance and its deregulation in cancer. Recent progress includes the identification of many novel SUMO substrates with important roles in cell cycle progression using proteomic approaches, and the demonstration that different mouse cancer models are dependent on a functioning SUMOylation system. Switching of SUMOylation in these cancer models caused a proliferation block of the cancer cells, showing that SUMO conjugating enzymes are potential drug targets. Europe PMC Funders Group Twenty years of SUMO research in cell cycle controlSUMO was linked to cell cycle progression even before the identification of the small protein modifier itself. Twenty years ago, the yeast SUMO conjugating enzyme Ubc9 was first proposed to be a ubiquitin conjugating enzyme. Ubc9 was s...

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“…The exact role of Fen1 in replication fork movement upon DNA damage is not yet known. A reasonable model describes Fen1 to play a role in the conversion of stalled replication forks into recombination substrates, which are involved in repairing collapsed replication forks (Henneke et al, 2003;Sharma et al, 2004). Irrespective of the exact mechanism of cellular recovery from DNA replication blockage, the inability of MEFs lacking p53 to upregulate Fen1 might cause accumulation of arrested replication forks, nuclease attack at collapsed forks and the formation of lethal DNA double-strand breaks.…”

Section: Fen1 Is Induced P53 Dependently M Christmann Et Almentioning

confidence: 99%

Fen1 is induced p53 dependently and involved in the recovery from UV-light-induced replication inhibition

Christmann¹,

Tomičić²,

Origer³

et al. 2005

Oncogene

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Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation

Cited by 101 publications

References 57 publications

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Fen1 is induced p53 dependently and involved in the recovery from UV-light-induced replication inhibition

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