Role of condensates in modulating DNA repair pathways and its implication for chemoresistance

Dall'Agnese, Giuseppe; Dall’Agnese, Alessandra; Banani, Salman F.; Codrich, Marta; Malfatti, Matilde Clarissa; Antoniali, Giulia; Tell, Gianluca

doi:10.1016/j.jbc.2023.104800

Cited by 13 publications

(2 citation statements)

References 167 publications

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“…Specifically, APE1 has been demonstrated to be able to cleave abasic RNA [15] and damaged ribonucleotides embedded in DNA [17,18], revealing it as an efficient endoribonuclease. Furthermore, only in the last few years, in concomitance with its novel and unsuspected involvement in the RNA metabolism, it has been described that APE1 can be present in subcellular condensates formed through liquid-liquid phase separation mechanisms (LLPS) [19][20][21] and can be secreted by tumoral cells through extracellular vesicles (EVs) [22].…”

Section: A Brief Introduction To Ape1 Biology and Different Functionsmentioning

confidence: 99%

Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons

Malfatti,

Bellina,

Antoniali

et al. 2023

Cells

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APE1 is an essential endodeoxyribonuclease of the base excision repair pathway that maintains genome stability. It was identified as a pivotal factor favoring tumor progression and chemoresistance through the control of gene expression by a redox-based mechanism. APE1 is overexpressed and serum-secreted in different cancers, representing a prognostic and predictive factor and a promising non-invasive biomarker. Strategies directly targeting APE1 functions led to the identification of inhibitors showing potential therapeutic value, some of which are currently in clinical trials. Interestingly, evidence indicates novel roles of APE1 in RNA metabolism that are still not fully understood, including its activity in processing damaged RNA in chemoresistant phenotypes, regulating onco-miRNA maturation, and oxidized RNA decay. Recent data point out a control role for APE1 in the expression and sorting of onco-miRNAs within secreted extracellular vesicles. This review is focused on giving a portrait of the pros and cons of the last two decades of research aiming at the identification of inhibitors of the redox or DNA-repair functions of APE1 for the definition of novel targeted therapies for cancer. We will discuss the new perspectives in cancer therapy emerging from the unexpected finding of the APE1 role in miRNA processing for personalized therapy.

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Section: A Brief Introduction To Ape1 Biology and Different Functionsmentioning

confidence: 99%

Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons

Malfatti,

Bellina,

Antoniali

et al. 2023

Cells

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“…This is a very compelling possibility, as the LLPS-driven formation of various membrane-less organelles (MLOs) and biomolecular condensates is considered now as one of the crucial organizing principles of the intracellular space responsible for regulation and control of numerous cellular processes 107 . Among these MLOs related to the subject of this study are the DNA repair foci, formation of which represents a part of the DNA damage response 108 , 109 , 110 , 111 , 112 ; Promyelocytic leukemia Nuclear Bodies (PML NBs) that are physically associated with chromatin 113 and related to the chromatin function; liquid condensates on DNA/RNA matrices containing related proteins and G-quadruplexes (G4s) and responsible for reparation, transcription, genome integrity maintenance, and chromatin remodeling 114 ; nuclear condensates containing polycomb group (PcG) proteins that contribute to the reshaping of chromatin architecture under the physiological and pathological conditions 115 ; and intrinsic chromatin condensates related to various chromatin-centric processes, such as transcription, loop extrusion, and remodeling 116 to name a few. Therefore, it is likely that the LLPS-driven formation of biomolecular condensates containing this protein and nucleic acids can play a role in complex functionality of PALB2-DBD and similar regions of other DNA-binding IDRs,…”

Section: Discussionmentioning

confidence: 99%

The PALB2 DNA-binding domain is an intrinsically disordered recombinase

Korolev,

Kyriukha,

Redington

et al. 2023

Preprint

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The Partner and Localizer of BRCA2 (PALB2) tumor suppressor is a scaffold protein that links BRCA1 with BRCA2 to initiate homologous recombination (HR). PALB2 interaction with DNA strongly enhances HR efficiency. The PALB2 DNA-binding domain (PALB2-DBD) supports DNA strand exchange, a complex multistep reaction supported by only a few protein families such as RecA-like recombinases or Rad52. The mechanisms of PALB2 DNA binding and strand exchange are unknown. We performed circular dichroism, electron paramagnetic spectroscopy, and small-angle X-ray scattering analyses and determined that PALB2-DBD is intrinsically disordered, even when bound to DNA. The intrinsically disordered nature of this domain was further supported by bioinformatics analysis. Intrinsically disordered proteins (IDPs) are prevalent in the human proteome and have many important biological functions. The complexity of the strand exchange reaction significantly expands the functional repertoire of IDPs. The results of confocal single-molecule FRET indicated that PALB2-DBD binding leads to oligomerization-dependent DNA compaction. We hypothesize that PALB2-DBD uses a chaperone-like mechanism to aid formation and resolution of complex DNA and RNA multichain intermediates during DNA replication and repair. Since PALB2-DBD alone or within the full-length PALB2 is predicted to have strong liquid-liquid phase separation (LLPS) potential, protein-nucleic acids condensates are likely to play a role in complex functionality of PALB2-DBD. Similar DNA-binding intrinsically disordered regions may represent a novel class of functional domains that evolved to function in eukaryotic nucleic acid metabolism complexes.

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Genome maintenance meets mechanobiology

Spegg

Altmeyer

2023

Chromosoma

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Genome stability is key for healthy cells in healthy organisms, and deregulated maintenance of genome integrity is a hallmark of aging and of age-associated diseases including cancer and neurodegeneration. To maintain a stable genome, genome surveillance and repair pathways are closely intertwined with cell cycle regulation and with DNA transactions that occur during transcription and DNA replication. Coordination of these processes across different time and length scales involves dynamic changes of chromatin topology, clustering of fragile genomic regions and repair factors into nuclear repair centers, mobilization of the nuclear cytoskeleton, and activation of cell cycle checkpoints. Here, we provide a general overview of cell cycle regulation and of the processes involved in genome duplication in human cells, followed by an introduction to replication stress and to the cellular responses elicited by perturbed DNA synthesis. We discuss fragile genomic regions that experience high levels of replication stress, with a particular focus on telomere fragility caused by replication stress at the ends of linear chromosomes. Using alternative lengthening of telomeres (ALT) in cancer cells and ALT-associated PML bodies (APBs) as examples of replication stress-associated clustered DNA damage, we discuss compartmentalization of DNA repair reactions and the role of protein properties implicated in phase separation. Finally, we highlight emerging connections between DNA repair and mechanobiology and discuss how biomolecular condensates, components of the nuclear cytoskeleton, and interfaces between membrane-bound organelles and membraneless macromolecular condensates may cooperate to coordinate genome maintenance in space and time.

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Role of condensates in modulating DNA repair pathways and its implication for chemoresistance

Cited by 13 publications

References 167 publications

Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons

Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons

The PALB2 DNA-binding domain is an intrinsically disordered recombinase

Genome maintenance meets mechanobiology

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