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Cells
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DNA Double-Strand Break Repair and Its Clinical Implications
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DNA Double-Strand Break Repair and Its Clinical Implications

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell and Gene Therapy".

Deadline for manuscript submissions: closed (25 May 2023) | Viewed by 6786

Special Issue Editor

Dr. Huiming Lu

E-Mail Website
Guest Editor
Division of Molecular Radiation Biology, Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA
Interests: DNA double-strand break repair; DNA damage response; genome stability; RecQ helicases; DNA-PK

Special Issue Information

Dear Colleagues,
DNA double-strand break (DSB), arising from exogenous and endogenous stresses or cellular programmed activities, is the most lethal DNA lesion in cells, since unrepaired or incorrectly repaired DSB results in genome instability, cellular senescence or cell death, which further promotes tumorigenesis, genetic disorders and neurodegenerative diseases. After several decades’ study, at least four pathways have been discovered in mammalian cells to deal with this type of DNA lesion, including two major pathways, non-homologous end joining (NHEJ) and homologous recombination (HR), as well as two minor pathways, microhomology-mediated end joining (MMEJ) and single-strand annealing (SSA). Although HR and NHEJ have been extensively studied, many new important players and regulatory mechanisms are still being discovered, filling the gap in understanding the cellular process. Recently, the important roles for MMEJ and SSA in tumorigenesis and clinical application are attracting more and more attention, but it has to be noted that the knowledge of these two pathways are quite limited. For an example, the major players in these two processes have not been clearly defined. In addition, it is also of importance to understand mechanisms how cells pick up a right pathway to repair DSB. Usually, HR is a high fidelity DSB repair pathway because it utilizes intact sister chromatin DNA as template to repair broken one. Whereas, another three are error-prone, especially MMEJ and SSA, which are instinctively mutagenic since large deletions or insertions often occur during repair. Therefore, tight regulation of pathway choice for DSB repair is required to maintain genome stability and cell health. Moreover, understanding molecular mechanisms of DSB repair and pathway choice also strongly promotes development of drug or therapeutic approaches in cancer therapy, especially for personalized therapy. 
This Special Issue calls for papers that focus on mechanisms of DSB repair and pathway choice, biological consequences caused by DSB repair deficiency, and clinical implications. 
We look forward to your participation. 

Dr. Huiming Lu
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • DNA double-strand break
  • pathway choice
  • homologous recombination
  • non-homologous end joining
  • microhomology-mediated end joining
  • single-strand annealing
  • premature aging
  • tumorigenesis
  • neurodegeneration

Published Papers (3 papers)

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Research

21 pages, 3250 KiB  
Article
Poly(ADP-Ribose) Polymerase-1 Lacking Enzymatic Activity Is Not Compatible with Mouse Development
by Tatiana Kamaletdinova, Wen Zong, Pavel Urbánek, Sijia Wang, Mara Sannai, Paulius Grigaravičius, Wenli Sun, Zahra Fanaei-Kahrani, Aswin Mangerich, Michael O. Hottiger, Tangliang Li and Zhao-Qi Wang
Cells 2023, 12(16), 2078; https://doi.org/10.3390/cells12162078 - 16 Aug 2023
Viewed by 1271
Abstract
Poly(ADP-ribose) polymerase-1 (PARP1) binds DNA lesions to catalyse poly(ADP-ribosyl)ation (PARylation) using NAD+ as a substrate. PARP1 plays multiple roles in cellular activities, including DNA repair, transcription, cell death, and chromatin remodelling. However, whether these functions are governed by the enzymatic activity or scaffolding [...] Read more.
Poly(ADP-ribose) polymerase-1 (PARP1) binds DNA lesions to catalyse poly(ADP-ribosyl)ation (PARylation) using NAD+ as a substrate. PARP1 plays multiple roles in cellular activities, including DNA repair, transcription, cell death, and chromatin remodelling. However, whether these functions are governed by the enzymatic activity or scaffolding function of PARP1 remains elusive. In this study, we inactivated in mice the enzymatic activity of PARP1 by truncating its C-terminus that is essential for ART catalysis (PARP1ΔC/ΔC, designated as PARP1-ΔC). The mutation caused embryonic lethality between embryonic day E8.5 and E13.5, in stark contrast to PARP1 complete knockout (PARP1−/−) mice, which are viable. Embryonic stem (ES) cell lines can be derived from PARP1ΔC/ΔC blastocysts, and these mutant ES cells can differentiate into all three germ layers, yet, with a high degree of cystic structures, indicating defects in epithelial cells. Intriguingly, PARP1-ΔC protein is expressed at very low levels compared to its full-length counterpart, suggesting a selective advantage for cell survival. Noticeably, PARP2 is particularly elevated and permanently present at the chromatin in PARP1-ΔC cells, indicating an engagement of PARP2 by non-enzymatic PARP1 protein at the chromatin. Surprisingly, the introduction of PARP1-ΔC mutation in adult mice did not impair their viability; yet, these mutant mice are hypersensitive to alkylating agents, similar to PARP1−/− mutant mice. Our study demonstrates that the catalytically inactive mutant of PARP1 causes the developmental block, plausibly involving PARP2 trapping. Full article
(This article belongs to the Special Issue DNA Double-Strand Break Repair and Its Clinical Implications)
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12 pages, 3165 KiB  
Article
Black Phosphorus Quantum Dots Enhance the Radiosensitivity of Human Renal Cell Carcinoma Cells through Inhibition of DNA-PKcs Kinase
by Yue Lang, Xin Tian, Hai-Yue Dong, Xiang-Xiang Zhang, Lan Yu, Ming Li, Meng-Meng Gu, Dexuan Gao and Zeng-Fu Shang
Cells 2022, 11(10), 1651; https://doi.org/10.3390/cells11101651 - 16 May 2022
Cited by 3 | Viewed by 2150
Abstract
Renal cell carcinoma (RCC) is one of the most aggressive urological malignancies and has a poor prognosis, especially in patients with metastasis. Although RCC is traditionally considered to be radioresistant, radiotherapy (RT) is still a common treatment for palliative management of metastatic RCC. [...] Read more.
Renal cell carcinoma (RCC) is one of the most aggressive urological malignancies and has a poor prognosis, especially in patients with metastasis. Although RCC is traditionally considered to be radioresistant, radiotherapy (RT) is still a common treatment for palliative management of metastatic RCC. Novel approaches are urgently needed to overcome radioresistance of RCC. Black phosphorus quantum dots (BPQDs) have recently received great attention due to their unique physicochemical properties and good biocompatibility. In the present study, we found that BPQDs enhance ionizing radiation (IR)-induced apoptotic cell death of RCC cells. BPQDs treatment significantly increases IR-induced DNA double-strand breaks (DSBs), as indicated by the neutral comet assay and the DSBs biomarkers γH2AX and 53BP1. Mechanistically, BPQDs can interact with purified DNA–protein kinase catalytic subunit (DNA-PKcs) and promote its kinase activity in vitro. BPQDs impair the autophosphorylation of DNA-PKcs at S2056, and this site phosphorylation is essential for efficient DNA DSBs repair and the release of DNA-PKcs from the damage sites. Consistent with this, BPQDs suppress nonhomologous end-joining (NHEJ) repair and lead to sustained high levels of autophosphorylated DNA-PKcs on the damaged sites. Moreover, animal experiments indicate that the combined approach with both BPQDs and IR displays better efficacy than monotreatment. These findings demonstrate that BPQDs have potential applications in radiosensitizing RCC cells. Full article
(This article belongs to the Special Issue DNA Double-Strand Break Repair and Its Clinical Implications)
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20 pages, 3705 KiB  
Article
GM-CSF Protects Macrophages from DNA Damage by Inducing Differentiation
by Tania Vico, Catrin Youssif, Fathema Zare, Mònica Comalada, Carlos Sebastian, Jorge Lloberas and Antonio Celada
Cells 2022, 11(6), 935; https://doi.org/10.3390/cells11060935 - 09 Mar 2022
Cited by 6 | Viewed by 2799
Abstract
At inflammatory loci, pro-inflammatory activation of macrophages produces large amounts of reactive oxygen species (ROS) that induce DNA breaks and apoptosis. Given that M-CSF and GM-CSF induce two different pathways in macrophages, one for proliferation and the other for survival, in this study [...] Read more.
At inflammatory loci, pro-inflammatory activation of macrophages produces large amounts of reactive oxygen species (ROS) that induce DNA breaks and apoptosis. Given that M-CSF and GM-CSF induce two different pathways in macrophages, one for proliferation and the other for survival, in this study we wanted to determine if these growth factors are able to protect against the DNA damage produced during macrophage activation. In macrophages treated with DNA-damaging agents we found that GM-CSF protects better against DNA damage than M-CSF. Treatment with GM-CSF resulted in faster recovery of DNA damage than treatment with M-CSF. The number of apoptotic cells induced after DNA damage was higher in the presence of M-CSF. Protection against DNA damage by GM-CSF is not related to its higher capacity to induce proliferation. GM-CSF induces differentiation markers such as CD11c and MHCII, as well as the pro-survival Bcl-2A1 protein, which make macrophages more resistant to DNA damage. Full article
(This article belongs to the Special Issue DNA Double-Strand Break Repair and Its Clinical Implications)
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