UHRF1 is a genome caretaker that facilitates the DNA damage response to γ-irradiation

Mistry, Helena; Tamblyn, Laura; Butt, Hussein; Sisgoreo, Daniel; Gracias, Aileen; Larin, Meghan; Gopalakrishnan, Kalpana; Hande, M. Prakash; McPherson, J. Peter

doi:10.1186/2041-9414-1-7

Cited by 30 publications

(36 citation statements)

References 43 publications

(69 reference statements)

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“…As shown in Fig. 1A, we found that the UHRF1 protein level is also regulated in response to DNA damage, i.e., the UHRF1 protein level is reduced upon UV irradiation, consistent with a proposed role of UHRF1 in the DDR (16,20,(25)(26)(27). The reduction of UHRF1 in the DDR is likely attributable to proteasome-mediated degradation, because the proteasome inhibitor MG132 restored Interestingly, the USP7 level and its interaction with UHRF1 remained unaltered in the DDR (Fig.…”

Section: Resultssupporting

confidence: 60%

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DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase

Chen

Inuzuka

et al. 2013

Molecular and Cellular Biology

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f UHRF1 (ubiquitin-like, with PHD and RING finger domains 1) is a critical epigenetic player involved in the maintenance of DNA methylation patterns during DNA replication. Dysregulation of the UHRF1 level is implicated in cancer onset, metastasis, and tumor recurrence. Previous studies demonstrated that UHRF1 can be stabilized through USP7-mediated deubiquitylation, but the mechanism through which UHRF1 is ubiquitylated is still unknown. Here we show that proteasomal degradation of UHRF1 is mediated by the SCF ␤-TrCP E3 ligase. Through bioinformatic and mutagenesis studies, we identified a functional DSG degron in the UHRF1 N terminus that is necessary for UHRF1 stability regulation. We further show that UHRF1 physically interacts with ␤-TrCP1 in a manner dependent on phosphorylation of serine 108 (S108 UHRF1 ) within the DSG degron. Furthermore, we demonstrate that S108 UHRF1 phosphorylation is catalyzed by casein kinase 1 delta (CK1␦) and is important for the recognition of UHRF1 by SCF ␤-TrCP . Importantly, we demonstrate that UHRF1 degradation is accelerated in response to DNA damage, coincident with enhanced S108 UHRF1 phosphorylation. Taken together, our data identify SCF ␤-TrCP as a bona fide UHRF1 E3 ligase important for regulating UHRF1 steady-state levels both under normal conditions and in response to DNA damage.T he epigenetic regulator UHRF1 is composed of multiple functional domains, including the UBL, Tudor, PHD, SRA, and RING domains, which are responsible for the recognition of histone and DNA methylation as well as ubiquitylation by UHRF1. These domains underlie the ability of UHRF1 to play a role in multiple processes, such as maintenance of DNA methylation, heterochromatin organization, and gene transcription (1-8). Previous studies identified a correlation between UHRF1 overexpression and cancer progression and metastasis, possibly through silencing of various tumor suppressor genes (9-12). Moreover, UHRF1 is implicated in apoptosis in response to DNA damage. Murine embryonic stem cells with targeted disruption of the Uhrf1 gene are hypersensitive to DNA-damaging agents (13). Similarly, knockdown of UHRF1 in HEK293 and WI-38 cells also renders these cells hypersensitive to X rays, UV light, and hydroxyurea (14). More recently, UHRF1 has also been shown to facilitate the DNA damage response (DDR) to gamma irradiation (15, 16). Consistently, DNA damage results in a decrease in the UHRF1 mRNA as well as protein level (1). More recent studies suggest that UHRF1 turnover is controlled by proteasome-mediated degradation. These studies identified the deubiquitylase USP7 in the regulation of the UHRF1 level in vivo (17-19). Specifically, UHRF1 is protected from proteasome-mediated degradation through its association with the deubiquitylase USP7, in a cell cycle-dependent manner. At the M phase of the cell cycle, USP7 disassociates from UHRF1, thus exposing UHRF1 to proteasomal degradation (18). Importantly, manipulating the UHRF1 level in cells has been shown to affect cell proliferation (11,18,20...

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Section: Resultssupporting

confidence: 60%

“…Similarly, knockdown of UHRF1 in HEK293 and WI-38 cells also renders these cells hypersensitive to X rays, UV light, and hydroxyurea (14). More recently, UHRF1 has also been shown to facilitate the DNA damage response (DDR) to gamma irradiation (15,16). Consistently, DNA damage results in a decrease in the UHRF1 mRNA as well as protein level (1).…”

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confidence: 58%

DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase

Chen

Inuzuka

et al. 2013

Molecular and Cellular Biology

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“…UHRF1 depletion from cancer cells results in a variety of phenotypes, including cell cycle arrest (Li et al, 2011;Tien et al, 2011), apoptosis (Tien et al, 2011), loss of contact inhibition (Hopfner et al, 2002) and increased sensitivity to DNA-damaging agents (Arima et al, 2004;Mistry et al, 2010;Muto et al, 2002). Similar phenotypes have also been reported for DNMT1-deficient cells (Chen et al, 2007;Karpf and Matsui, 2005;Milutinovic et al, 2003;Unterberger et al, 2006;Vijayaraghavalu et al, 2013), suggesting DNA hypomethylation as the underlying cause of these phenotypes.…”

Section: Introductionsupporting

confidence: 50%

DNA hypomethylation induces a DNA replication-associated cell cycle arrest to block hepatic outgrowth in uhrf1 mutant zebrafish embryos

et al. 2015

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UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) recruits DNMT1 to hemimethylated DNA during replication and is essential for maintaining DNA methylation. uhrf1 mutant zebrafish have global DNA hypomethylation and display embryonic defects, including a small liver, and they die as larvae. We make the surprising finding that, despite their reduced organ size, uhrf1 mutants express high levels of genes controlling S-phase and have many more cells undergoing DNA replication, as measured by BrdU incorporation. In contrast to wild-type hepatocytes, which are continually dividing during hepatic outgrowth and thus dilute the BrdU label, uhrf1 mutant hepatocytes retain BrdU throughout outgrowth, reflecting cell cycle arrest. Pulse-chase-pulse experiments with BrdU and EdU, and DNA content analysis indicate that uhrf1 mutant cells undergo DNA re-replication and that apoptosis is the fate of many of the rereplicating and arrested hepatocytes. Importantly, the DNA rereplication phenotype and hepatic outgrowth failure are preceded by global loss of DNA methylation. Moreover, uhrf1 mutants are phenocopied by mutation of dnmt1, and Dnmt1 knockdown in uhrf1 mutants enhances their small liver phenotype. Together, these data indicate that unscheduled DNA replication and failed cell cycle progression leading to apoptosis are the mechanisms by which DNA hypomethylation prevents organ expansion in uhrf1 mutants. We propose that cell cycle arrest leading to apoptosis is a strategy that restricts propagation of epigenetically damaged cells during embryogenesis.

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“…7,8,44,51,57,58 Thus, it was shown to be an important factor to facilitate DNA replication, cell cycle progression, transcriptional repression, and DNA damage response. 2,53,[59][60][61] This variety of functions argues for different states of the protein that provide distinct binding interfaces not only for histone and DNA modifications but also for specific protein interaction partners (Fig. 5).…”

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confidence: 99%

Conserved linker regions and their regulation determine multiple chromatin-binding modes of UHRF1

Tauber

Fischle

2015

Nucleus

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U biquitin-like with PHD and RING Finger domains 1 (UHRF1) is an important nuclear protein that is mutated and aberrantly expressed in many tumors. The protein integrates different chromatin modifications and is essential for their maintenance throughout the cell cycle. Separate chromatinbinding modules of UHRF1 have been studied on a functional and structural level. The unmodified N-terminus of histone H3 is recognized by a PHD domain, while a TTD domain specifically interacts with histone H3 Lysine 9 trimethylation. A SRA region binds hemimethylatd DNA. Emerging evidence indicates that the modules of UHRF1 do not act independently of each other but establish complex modes of interaction with patterns of chromatin modifications. This multivalent readout is regulated by allosteric binding of phosphatidylinositol 5-phosphate to a region outside the PHD, TTD and SRA domains as well as by phosphorylation of one of the linker regions connecting these modules. Here, we summarize the current knowledge on UHRF1 chromatin interaction and introduce a novel model of conformational transitions of the protein that are directed by the flexible and highly charged linker regions. We propose that these are essential in setting up defined structural states of the protein where different domains or combinations thereof are available for binding chromatin modifications or are prevented from doing so. Lastly, we suggest that controlled tuning of intramolecular linker interactions by ligands and posttranslational modifications establishes a rational framework for comprehending UHRF1 regulation and putatively the working mode of other chromatin factors in different physiological contexts.

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UHRF1 is a genome caretaker that facilitates the DNA damage response to γ-irradiation

Cited by 30 publications

References 43 publications

DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase

DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase

DNA hypomethylation induces a DNA replication-associated cell cycle arrest to block hepatic outgrowth in uhrf1 mutant zebrafish embryos

Conserved linker regions and their regulation determine multiple chromatin-binding modes of UHRF1

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UHRF1 is a genome caretaker that facilitates the DNA damage response to γ-irradiation

Cited by 30 publications

References 43 publications

DNA Damage Regulates UHRF1 Stability via the SCFβ-TrCP E3 Ligase

DNA Damage Regulates UHRF1 Stability via the SCFβ-TrCP E3 Ligase

DNA hypomethylation induces a DNA replication-associated cell cycle arrest to block hepatic outgrowth in uhrf1 mutant zebrafish embryos

Conserved linker regions and their regulation determine multiple chromatin-binding modes of UHRF1

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DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase

DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase