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Review
. 2023 Jun;299(6):104800.
doi: 10.1016/j.jbc.2023.104800. Epub 2023 May 9.

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

Giuseppe Dall'Agnese  1 , Alessandra Dall'Agnese  2 , Salman F Banani  3 , Marta Codrich  4 , Matilde Clarissa Malfatti  4 , Giulia Antoniali  4 , Gianluca Tell  5
Affiliations
Review

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

Giuseppe Dall'Agnese et al. J Biol Chem. 2023 Jun.

Abstract

For cells, it is important to repair DNA damage, such as double-strand and single-strand DNA breaks, because unrepaired DNA can compromise genetic integrity, potentially leading to cell death or cancer. Cells have multiple DNA damage repair pathways that have been the subject of detailed genetic, biochemical, and structural studies. Recently, the scientific community has started to gain evidence that the repair of DNA double-strand breaks may occur within biomolecular condensates and that condensates may also contribute to DNA damage through concentrating genotoxic agents used to treat various cancers. Here, we summarize key features of biomolecular condensates and note where they have been implicated in the repair of DNA double-strand breaks. We also describe evidence suggesting that condensates may be involved in the repair of other types of DNA damage, including single-strand DNA breaks, nucleotide modifications (e.g., mismatch and oxidized bases), and bulky lesions, among others. Finally, we discuss old and new mysteries that could now be addressed considering the properties of condensates, including chemoresistance mechanisms.

Keywords: DNA damage response; chemoresistance; condensates; internal disordered regions; liquid-liquid phase separation.

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Conflict of interest statement

Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1
Figure 1
Schematic overview of different biomolecular condensates identified in eukaryotic cells.A, Representation of different biomolecular condensates that can be found in the cytoplasm (Stress granules, signaling condensates), nucleus (Transcriptional condensates, Splicing condensates, DNA Damage Repair condensates, Nucleolus, Heterochromatin condensates, miRNA processing condensates, Cajal bodies) and in between (nucleopore condensates) of eukaryotic cells. B, Focus on transcription-associated condensates: Nucleolus (constituted by the FC where the active transcription of ribosomal DNA occurs through RNA Polymerase I; the DFC where the ribosomal RNA processing is orchestrated and the GC where take place the assembly of ribosomal subunits), Transcriptional condensates (where the initiation complex of RNA Polymerase II and several Transcription Factors and co-activators can be found), Splicing condensate (where elongating RNA polymerase II is recruited allowing for co-transcriptional splicing) and the DDR condensates (formed upon DNA damage thanks to the recruitment of DNA repair enzymes due to the transcriptional activity of RNA Polymerase II). DDR, DNA Damage Repair; DFC, Dense Fibrillar Component; FC, Fibrillar Component; GC, Granular Component.
Figure 2
Figure 2
Liquid-Liquid Phase Separation model. Visual representation of the Liquid-Liquid Phase Separation model describable with a binodal curve (redcurve) that separates the 1 versus 2 phase regimes as a function of biomolecule concentration (x-axis) and system parameters such as temperature, pH, and salt’s concentration (y-axis). A lower concentration of biomolecules (dark green) will allow them to be homogeneously mixed in the solution (bottom left panel—widely diffuse green color) whereas higher concentrations will induce a phase separation leading to the formation of a more enriched (green spheres) and a less concentrated (light green or white) regions (central panel) until the condensed fraction will prevail (bottom right panel—dark green color with many biomolecules).
Figure 3
Figure 3
Overview of DDR. Schematic representation of DNA lesions caused by different damage sources and of respective DNA repair pathways. The major proteins involved in the DNA repair pathways are shown. BER, base excision repair; DSBs, double-strand breaks; HR, homologous recombination; MMR, mismatch repair; NER, nucleotide excision repair; NHEJ, non-homologous end joining; SSBs, single-strand breaks.
Figure 4
Figure 4
Local chromatin organization and the role of RNA transcription and PARylation in DNA damage response. The spatial organization of chromosomes into compartmentalized functional units called TADs, strictly depends on several proteins as well as RNAs produced by active transcription, which are assembled through nucleation mechanisms involving LLPS. Upon DNA damage, proteins undergoing LLPS and DDR proteins are recruited in stress-induced transcription-associated LLPS. DNA PARylated at the site of damage, as well as the nascent dilncRNA from Pol II, work for the recruitment of several ribonucleoproteins (hnRNPs), and for the induction of DNA repair. Moreover, a local chromatin organization is promoted through RNA modifications and R-loops generation. These processes encourage synchronously the signaling of the DNA repair and the activation of DDR pathways. Specifically, DNA-PK, ATM, and ATR protein kinases phosphorylate H2A.x stimulating the generation of γH2A.x foci, which opens chromatin for repair complex formation and signals the presence of DNA damage by activation of p53 and BRCA1. Both ATM and ATR are also responsible for the phosphorylation of p53 targeting it to the nucleus. While ATM is mainly involved in DSBs damage-induced repair, ATR is responsible for coordinating the repair of DSBs induced by replicative stress. Moreover, γH2A.x stimulates PARP1 which PARylates p53 protein. The effects of these orchestrated processes include DNA repair, cell cycle arrest, and lastly apoptosis. DDR, DNA Damage Repair; DSB, double-strand breaks; LLPS, liquid-liquid phase separation; TAD, topologically associating domains.
Figure 5
Figure 5
IDR analysis on the main DNA damage repair enzymes.A, Pie-charts representing the percentage of DNA repair proteins with IDR longer than 50 amino acids. Within the whole proteome, 82% of proteins seems to have IDR longer than 50 amino acids (top left panel) whereas, out of 567 proteins belonging to different DDR pathways taken into consideration, 538 (94.5%) possess IDRs longer than 50 amino acids (top right panel). Among the 567 proteins investigated, 197 proteins belong to the Nucleotide Excision Repair (NER) pathway (bottom left), 78 of the Base Excision Repair (BER) pathway (bottom center) and 52 of the Mismatch Repair (MMR) pathway (bottom right), which showed to have 180, 71 and 48 proteins with IDR(s) longer than 50 amino acids respectively. IDRs were mapped using Metapredict (130), a consensus predictor that integrates several disorder predictors. IDRs were defined using a threshold of 0.2, which has been successfully used previously (165) and is within the recommended range of cutoffs suggested by the developers of the algorithm. B, Representative examples of IDR prediction of DSB enzymes TopBP1, 53BP1, RAD52, and MRE11. C, Representative examples of IDR prediction of APE1 and UNG, belonging to the Base Excision Repair pathway, ERCC3, and ERCC6, belonging to the Nucleotide Excision Repair pathway, MLH1 and MSH4, belonging to the Mismatch Repair pathway. All predicted structures in (B) and (C) were obtained using Metapredict (130, 131); y-axes represent the disorder content whereas the x-axes represent the aminoacidic residues of the proteins; each line in the x-axes marks 50 residues; highlighted in red the predicted IDR longer than 50 amino acids. DDR, DNA Damage Repair; DSB, double-strand breaks; IDR, Intrinsically Disordered Region(s).
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