Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P

Mandal, Papita; Eswara, Karthik; Yerkesh, Zhadyra; Kharchenko, Vladlena; Zandarashvili, Levani; Szczepski, Kacper; Bensaddek, Dalila; Jaremko, Łukasz; Black, Ben E.; Fischle, Wolfgang

doi:10.1126/sciadv.abl9461

Cited by 3 publications

(2 citation statements)

References 75 publications

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“…UHRF1 acts to safeguard the genome by maintaining global DNA methylation profiles, silencing repetitive elements, and protecting chromatin from DNA damaging agents [168]. PtdIns5P interacts with a polybasic region (PBR) in the C-terminus of UHRF1 to induce a conformational change and rearrangement of its domains, allowing the tandem Tudor domain (TTD) in the N-terminus to bind more strongly to H3K9me3 [168,180]. Although the exact consequences of PtdIns5P interaction with UHRF1 in vivo are not clear, UHRF1 is often upregulated in tumour cells, and targeting the allosteric PtdIns5P interaction site may have therapeutic value.…”

Section: Nuclear Ppins and Their Role In Defining How Histone Modific...mentioning

confidence: 99%

Nuclear Phosphoinositides as Key Determinants of Nuclear Functions

Vidalle,

Sheth,

Fazio

et al. 2023

Biomolecules

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Polyphosphoinositides (PPIns) are signalling messengers representing less than five per cent of the total phospholipid concentration within the cell. Despite their low concentration, these lipids are critical regulators of various cellular processes, including cell cycle, differentiation, gene transcription, apoptosis and motility. PPIns are generated by the phosphorylation of the inositol head group of phosphatidylinositol (PtdIns). Different pools of PPIns are found at distinct subcellular compartments, which are regulated by an array of kinases, phosphatases and phospholipases. Six of the seven PPIns species have been found in the nucleus, including the nuclear envelope, the nucleoplasm and the nucleolus. The identification and characterisation of PPIns interactor and effector proteins in the nucleus have led to increasing interest in the role of PPIns in nuclear signalling. However, the regulation and functions of PPIns in the nucleus are complex and are still being elucidated. This review summarises our current understanding of the localisation, biogenesis and physiological functions of the different PPIns species in the nucleus.

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Section: Nuclear Ppins and Their Role In Defining How Histone Modific...mentioning

confidence: 99%

Nuclear Phosphoinositides as Key Determinants of Nuclear Functions

Vidalle,

Sheth,

Fazio

et al. 2023

Biomolecules

View full text Add to dashboard Cite

show abstract

“…Increased PI5P in the nucleus was shown to activate transcription through direct binding to the transcription factor TAF3 ( Stijf-Bultsma et al, 2015 ). Work from the lab of Wolfgang Fischle suggested PI5P allosterically activates the epigenetic regulator UHRF1, with PI5P inducing a state in UHRF1 that interacts more with methylated histones (H3K9me3) ( Gelato et al, 2014 ; Mandal et al, 2022 ). More recently, PI5P exogenously added to cells was shown to promote the degradation of UHRF1 ( Poli et al, 2023 ).…”

Section: Subcellular Localization Of Pi5p and Nuclear Pi5pmentioning

confidence: 99%

25 Years of PI5P

Rameh,

Blind

2023

Front. Cell Dev. Biol.

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The accidental discovery of PI5P (phosphatidylinositol-5-phosphate) was published 25 years ago, when PIP5K type II (phosphoinositide-4-phosphate 5-kinase) was shown to actually be a 4-kinase that uses PI5P as a substrate to generate PI(4,5)P2. Consequently, PIP5K type II was renamed to PI5P4K, or PIP4K for short, and PI5P became the last of the 7 signaling phosphoinositides to be discovered. Much of what we know about PI5P comes from genetic studies of PIP4K, as the pathways for PI5P synthesis, the downstream targets of PI5P and how PI5P affects cellular function all remain largely enigmatic. Nevertheless, PI5P and PI5P-dependent PI(4,5)P2 synthesis have been clearly implicated in metabolic homeostasis and in diseases such as cancer. Here, we review the past 25 years of PI5P research, with particular emphasis on the impact this small signaling lipid has on human health.

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Nuclear lipids in chromatin regulation: Biological roles, experimental approaches and existing challenges

Sayed,

Eswara,

Teles

et al. 2024

Biology of the Cell

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Lipids are crucial for various cellular functions. Besides the storage of energy equivalents, these include forming membrane bilayers and serving as signaling molecules. While significant progress has been made in the comprehension of the molecular and cellular biology of lipids, their functions in the cell nucleus remain poorly understood. The main role of the eukaryotic cell nucleus is to provide an environment for the storage and regulation of chromatin which is a complex of DNA, histones, and associated proteins. Recent studies suggest that nuclear lipids play a role in chromatin regulation and epigenetics. Here, we discuss various experimental methods in lipid‐chromatin research, including biophysical, structural, and cell biology approaches, pointing out their strengths and weaknesses. We take the view that nuclear lipids have a far more widespread impact on chromatin than is currently acknowledged. This gap in comprehension is mostly due to existing experimental challenges in the study of lipid‐chromatin biology. Several new, interdisciplinary approaches are discussed that could aid in elucidating the roles of nuclear lipids in chromatin regulation and gene expression.

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Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P

Cited by 3 publications

References 75 publications

Nuclear Phosphoinositides as Key Determinants of Nuclear Functions

Nuclear Phosphoinositides as Key Determinants of Nuclear Functions

25 Years of PI5P

Nuclear lipids in chromatin regulation: Biological roles, experimental approaches and existing challenges

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