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DNA Double-Strand Breaks Repair in Human Diseases - Pathophysiology and Implications for Therapy Based on Synthetic Lethality

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 7050

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Prof. Ireneusz Majsterek

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Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Lodz, Poland
Interests: DNA damage and repair; kinases inhibitors; Unfolded Protein Response; eye disease
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Dr. Tomasz Poplawski

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Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland
Interests: DNA damage and repair; DNA repair inhibitors; tryptophan metabolites; inflammatory diseases; thio-sugars
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Special Issue Information

Dear Colleagues,

DNA double-strand breaks (DSBs) are classified as one of the most serious DNA lesions. Unrepaired or miss-repaired DSBs potentially lead to genetic instability and/or even cell death. To survive and maintain normal phenotype cells have evolved specific pathways – collectively named the DNA-damage response (DDR) – to detect and repair DNA lesions. The part of DDR dealing with DSBs consist of two major, canonical pathways: non-homologous end joining (NHEJ) and homologous recombination repair (HRR). Also, cells capacity to deal with DSBs are supplemented by non-canonical pathways like microhomology-mediated end joining (MMEJ, also known as alternative NHEJ; alt-NHEJ, backup NHEJ) and single strand annealing (SSA). Given the role of these cellular pathways to maintain genetic stability it is clear that any malfunction will resulted in pathological phenotypes on cellular, tissue or whole organisms levels. A classic example, but not the exclusive one are cancers where NHEJ or HRR pathways are often disrupted or deregulated and non-canonical DSBs repair pathways rule the roost which increases genomic instability, consequently promoting cancer progression. These creates excellent therapeutic opportunity as DSBs repair components are promising target to be exploited by synthetic lethality approaches for the use of DDR inhibitors such as PARP inhibitors. It should be mentioned that using our knowledge about DSBs repair for therapeutical purposes are not limited only to cancers. For example human pathogens like Mycobacteria employ DSBs repair to survive during the pathogenic cycle. Moreover, deregulations of DSBs repair are reported in various auto-immunological diseases. This Special Issue objectives to provide novel insights into the molecular and cellular mechanisms underlying DSBs repair in the etiology of human diseases and to show novel therapeutic perspectives within DSBs repair.

Prof. Ireneusz Majsterek
Dr. Tomasz Poplawski
Guest Editors

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Keywords

non-homologous end joining (NHEJ)
homologous recombination repair (HRR)
genomic instability
synthetic lethality
alternative non-homologous end joining pathway (Alt-NHEJ)
DNA damage response (DDR)

Published Papers (3 papers)

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Research

13 pages, 1904 KiB

Open AccessArticle

RYBP Sensitizes Cancer Cells to PARP Inhibitors by Regulating ATM Activity

by Deanna V. Maybee, Alexandra Maria Psaras, Tracy A. Brooks and Mohammad A. M. Ali

Int. J. Mol. Sci. 2022, 23(19), 11764; https://doi.org/10.3390/ijms231911764 - 4 Oct 2022

Cited by 1 | Viewed by 1838

Abstract

Ring1 and YY1 Binding Protein (RYBP) is a member of the non-canonical polycomb repressive complex 1 (PRC1), and like other PRC1 members, it is best described as a transcriptional regulator. Previously, we showed that RYBP, along with other PRC1 members, is also involved in the DNA damage response. RYBP inhibits recruitment of breast cancer gene 1(BRCA1) complex to DNA damage sites through its binding to K63-linked ubiquitin chains. In addition, ataxia telangiectasia mutated (ATM) kinase serves as an important sensor kinase in early stages of DNA damage response. Here, we report that overexpression of RYBP results in inhibition in both ATM activity and recruitment to DNA damage sites. Cells expressing RYBP show less phosphorylation of the ATM substrate, Chk2, after DNA damage. Due to its ability to inhibit ATM activity, we find that RYBP sensitizes cancer cells to poly-ADP-ribose polymerase (PARP) inhibitors. Although we find a synergistic effect between PARP inhibitor and ATM inhibitor in cancer cells, this synergy is lost in cells expressing RYBP. We also show that overexpression of RYBP hinders cancer cell migration through, at least in part, ATM inhibition. We provide new mechanism(s) by which RYBP expression may sensitize cancer cells to DNA damaging agents and inhibits cancer metastasis. Full article

(This article belongs to the Special Issue DNA Double-Strand Breaks Repair in Human Diseases - Pathophysiology and Implications for Therapy Based on Synthetic Lethality)

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17 pages, 2192 KiB

Open AccessArticle

Wwox Binding to the Murine Brca1-BRCT Domain Regulates Timing of Brip1 and CtIP Phospho-Protein Interactions with This Domain at DNA Double-Strand Breaks, and Repair Pathway Choice

by Dongju Park, Mehdi Gharghabi, Colleen R. Reczek, Rebecca Plow, Charles Yungvirt, C. Marcelo Aldaz and Kay Huebner

Int. J. Mol. Sci. 2022, 23(7), 3729; https://doi.org/10.3390/ijms23073729 - 28 Mar 2022

Cited by 2 | Viewed by 2489

Abstract

Wwox-deficient human cells show elevated homologous recombination, leading to resistance to killing by double-strand break-inducing agents. Human Wwox binds to the Brca1 981-PPLF-984 Wwox-binding motif, likely blocking the pChk2 phosphorylation site at Brca1-S988. This phosphorylation site is conserved across mammalian species; the PPLF motif is conserved in primates but not in rodents. We now show that murine Wwox does not bind Brca1 near the conserved mouse Brca1 phospho-S971 site, leaving it open for Chk2 phosphorylation and Brca1 activation. Instead, murine Wwox binds to Brca1 through its BRCT domain, where pAbraxas, pBrip1, and pCtIP, of the A, B, and C binding complexes, interact to regulate double-strand break repair pathway response. In Wwox-deficient mouse cells, the Brca1-BRCT domain is thus accessible for immediate binding of these phospho-proteins. We confirm elevated homologous recombination in Wwox-silenced murine cells, as in human cells. Wwox-deficient murine cells showed increased ionizing radiation-induced Abraxas, Brca1, and CtIP foci and long resected single-strand DNA, early after ionizing radiation. Wwox deletion increased the basal level of Brca1-CtIP interaction and the expression level of the MRN-CtIP protein complex, key players in end-resection, and facilitated Brca1 release from foci. Inhibition of phospho-Chk2 phosphorylation of Brca1-S971 delays the end-resection; the delay of premature end-resection by combining Chk2 inhibition with ionizing radiation or carboplatin treatment restored ionizing radiation and platinum sensitivity in Wwox-deficient murine cells, as in human cells, supporting the use of murine in vitro and in vivo models in preclinical cancer treatment research. Full article

(This article belongs to the Special Issue DNA Double-Strand Breaks Repair in Human Diseases - Pathophysiology and Implications for Therapy Based on Synthetic Lethality)

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11 pages, 3118 KiB

Open AccessArticle

Poly ADP Ribose Polymerase Inhibitor Olaparib Targeting Microhomology End Joining in Retinoblastoma Protein Defective Cancer: Analysis of the Retinoblastoma Cell-Killing Effects by Olaparib after Inducing Double-Strand Breaks

by Yuning Jiang, Jason C. Yam and Wai Kit Chu

Int. J. Mol. Sci. 2021, 22(19), 10687; https://doi.org/10.3390/ijms221910687 - 1 Oct 2021

Cited by 3 | Viewed by 1978

Abstract

Retinoblastoma is the most common intraocular cancer in childhood. Loss of function in both copies of the RB1 gene is the causal mutation of retinoblastoma. Current treatment for retinoblastoma includes the use of chemotherapeutic agents, such as the DNA damaging agent etoposide, which is a topoisomerase II poison that mainly generates DNA double-strand breaks (DSBs) and genome instability. Unfaithful repairing of DSBs could lead to secondary cancers and serious side effects. Previously, we found that RB knocked-down mammalian cells depend on a highly mutagenic pathway, the micro-homology mediated end joining (MMEJ) pathway, to repair DSBs. Poly ADP ribose polymerase 1 (PARP1) is a major protein in promoting the MMEJ pathway. In this study, we explored the effects of olaparib, a PARP inhibitor, in killing retinoblastoma cells. Retinoblastoma cell line Y79 and primary retinoblastoma cells expressed the cone-rod homeobox protein (CRX), a photoreceptor-specific marker. No detectable RB expression was found in these cells. The co-treatment of olaparib and etoposide led to enhanced cell death in both the Y79 cells and the primary retinoblastoma cells. Our results demonstrated the killing effects in retinoblastoma cells by PARP inhibitor olaparib after inducing DNA double-strand breaks. The use of olaparib in combination with etoposide could improve the cell-killing effects. Thus, lower dosages of etoposide can be used to treat retinoblastoma, which would potentially lead to a lower level of DSBs and a relatively more stable genome. Full article

(This article belongs to the Special Issue DNA Double-Strand Breaks Repair in Human Diseases - Pathophysiology and Implications for Therapy Based on Synthetic Lethality)

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