Targeting enzyme aging

F, Becker; Rudolph, K. Lenhard

doi:10.1126/science.abf9566

Cited by 6 publications

(6 citation statements)

References 16 publications

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“…For example, aging correlates with the heterochromatin architecture ( Tsurumi and Li, 2012 ; Lee et al, 2020 ). Also, in aging, activity of various enzymes is known to undergo profound changes with cell state modifications ( Adelman and Britton, 1975 ; Becker and Rudolph, 2021 ). A part of aging-associated alteration of heterochromatin architecture might be attributed to the variation of enzymatic activity.…”

Section: Discussionmentioning

confidence: 99%

How enzymatic activity is involved in chromatin organization

Das

Sakaue

Shivashankar

et al. 2022

eLife

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Spatial organization of chromatin plays a critical role in genome regulation. Previously, various types of affnity mediators and enzymes have been attributed to regulate spatial organization of chromatin from a thermodynamics perspective. However, at the mechanistic level, enzymes act in their unique ways and perturb the chromatin. Here, we construct a polymer physics model following the mechanistic scheme of Topoisomerase-II, an enzyme resolving topological constraints of chromatin, and investigate how it affects interphase chromatin organization. Our computer simulations demonstrate Topoisomerase-II's ability to phase separate chromatin into eu- and heterochromatic regions with a characteristic wall-like organization of the euchromatic regions. We realized that the ability of the euchromatic regions to cross each other due to enzymatic activity of Topoisomerase-II induces this phase separation. This realization is based on the physical fact that partial absence of self-avoiding interaction can induce phase separation of a system into its self-avoiding and non-self-avoiding parts, which we reveal using a mean-field argument. Furthermore, motivated from recent experimental observations, we extend our model to a bidisperse setting and show that the characteristic features of the enzymatic activity driven phase separation survive there. The existence of these robust characteristic features, even under the non-localized action of the enzyme, highlights the critical role of enzymatic activity in chromatin organization.

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Section: Discussionmentioning

confidence: 99%

How enzymatic activity is involved in chromatin organization

Das

Sakaue

Shivashankar

et al. 2022

eLife

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“…For example, aging correlates with the heterochromatin architecture [46,47]. Also, in aging, activity of various enzymes is known to undergo profound changes with cell state modifications [48,49]. A part of aging-associated alteration of heterochromatin architecture might be attributed to the variation of enzymatic activity.…”

Section: Discussionmentioning

confidence: 99%

How enzymatic activity is involved in chromatin organization

R¹,

Sakaue²,

Shivashankar³

et al. 2021

Preprint

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Spatial organization of chromatin plays a critical role in genome regulation. Various types of affinity mediators and enzymes have been attributed to regulate spatial organization of chromatin from a thermodynamics perspective. However, at the mechanistic level, enzymes act in their unique ways. Here, we construct a polymer physics model following the mechanistic scheme of Topoisomerase-II, an enzyme resolving topological constraints of chromatin, and investigate its role on interphase chromatin organization. Our computer simulations demonstrate Topoisomerase-II's ability to phase separate chromatin into eu-and heterochromatic regions with a characteristic walllike organization of the euchromatic regions. Exploiting a mean-field framework, we argue that the ability of the euchromatic regions crossing each other due to enzymatic activity of Topoisomerase-II induces this phase separation. Motivated from a recent experimental observation on different structural states of the eu-and the heterochromatic units, we further extend our model to a bidisperse setting and show that the characteristic features of the enzymatic activity driven phase separation survives there. The existence of these characteristic features, even under the non-localized action of the enzyme, highlights the critical role of enzymatic activity in chromatin organization, and points out the importance of further experiments along this line.

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“…When discerning phenotypes at the organismal level, the inference of natural activities requires several levels of organisational hierarchy to be bridged (organism → organ → cell → subcellular compartment → molecular). Moreover, this hierarchy might at times need to be contextualised in light of organismal ageing and its effect on the rate of proteins’ natural activities (Becker & Rudolph, 2021). These realities turn phenotypic analyses into powerful validation tools when orthogonal data inform a hypothesis of a POI's natural activity but pose a formidable hindrance in the absence of such a hypothesis.…”

Section: Framework For Protein Function Assignmentmentioning

confidence: 99%

“…molecular). Moreover, this hierarchy might at times need to be contextualised in light of organismal ageing and its effect on the rate of proteins' natural activities (Becker & Rudolph, 2021). These realities turn phenotypic analyses into powerful validation tools when orthogonal data inform a hypothesis of a POI's natural activity but pose a formidable hindrance in the absence of such a hypothesis.…”

Section: The Function Of the Prion Proteinmentioning

confidence: 99%

The IDIP framework for assessing protein function and its application to the prion protein

et al. 2021

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The quest to determine the function of a protein can represent a profound challenge. Although this task is the mandate of countless research groups, a general framework for how it can be approached is conspicuously lacking. Moreover, even expectations for when the function of a protein can be considered to be 'known' are not well defined. In this review, we begin by introducing concepts pertinent to the challenge of protein function assignments. We then propose a framework for inferring a protein's function from four data categories: 'inheritance', 'distribution', 'interactions' and 'phenotypes' (IDIP). We document that the functions of proteins emerge at the intersection of inferences drawn from these data categories and emphasise the benefit of considering them in an evolutionary context. We then apply this approach to the cellular prion protein (PrP C ), well known for its central role in prion diseases, whose function continues to be considered elusive by many investigators. We document that available data converge on the conclusion that the function of the prion protein is to control a critical post-translational modification of the neural cell adhesion molecule in the context of epithelial-to-mesenchymal transition and related plasticity programmes. Finally, we argue that this proposed function of PrP C has already passed the test of time and is concordant with the IDIP framework in a way that other functions considered for this protein fail to achieve. We anticipate that the IDIP framework and the concepts analysed herein will aid the investigation of other proteins whose primary functional assignments have thus far been intractable.

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Targeting enzyme aging

Abstract: Age-associated changes in enzyme activity drive aging in mice and are possible drug targets

Cited by 6 publications

References 16 publications

How enzymatic activity is involved in chromatin organization

How enzymatic activity is involved in chromatin organization

How enzymatic activity is involved in chromatin organization

The IDIP framework for assessing protein function and its application to the prion protein

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