Abstract 4232: GFP imaging of DNA repair after UV irradiation of cancer cells

Although ubiquitin receptor Rad23 has been implicated in bringing ubiquitylated p53 to the proteasome, how Rad23 recognizes p53 remains unclear. We demonstrate that XPC, a Rad23-binding protein, regulates p53 turnover. p53 protein in XPC-deficient cells remains ubiquitylated, but its association with the proteasome is drastically reduced, indicating that XPC regulates a postubiquitylation event. Furthermore, we found that XPC participates in the MDM2-mediated p53 degradation pathway via direct interaction with MDM2. XPC W690S pathogenic mutant is specifically defective for MDM2 binding and p53 degradation. p53 is known to become stabilized following UV irradiation but can be rendered unstable by XPC overexpression, underscoring a critical role of XPC in p53 regulation. Elucidation of the proteolytic role of XPC in cancer cells will help to unravel the detailed mechanisms underlying the coordination of DNA repair and proteolysis.

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Imaging DNA Repair After UV Irradiation Damage of Cancer Cells in Gelfoam® Histoculture

3D Sponge-Matrix Histoculture - Methods in Molecular Biology ◽

10.1007/978-1-4939-7745-1_18 ◽

2018 ◽

pp. 199-203

Author(s):

Shinji Miwa ◽

Robert M. Hoffman

Keyword(s):

Dna Repair ◽

Cancer Cells ◽

Uv Irradiation ◽

Irradiation Damage

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Nuclear body phase separation drives telomere clustering in ALT cancer cells

Molecular Biology of the Cell ◽

10.1091/mbc.e19-10-0589 ◽

2020 ◽

Vol 31 (18) ◽

pp. 2048-2056 ◽

Cited By ~ 6

Author(s):

Huaiying Zhang ◽

Rongwei Zhao ◽

Jason Tones ◽

Michel Liu ◽

Robert L. Dilley ◽

...

Keyword(s):

Dna Repair ◽

Phase Separation ◽

Cancer Cells ◽

Nuclear Body ◽

Promyelocytic Leukemia ◽

Nuclear Bodies ◽

Telomere Elongation ◽

Alternative Lengthening ◽

Induce Phase Separation ◽

Induce Phase

A chemical dimerization approach is developed to induce phase separation of APB nuclear bodies involved in telomere elongation in alternative lengthening of telomeres (ALT) cancer cells. It reveals that ALT telomere-associated promyelocytic leukemia nuclear body (APB) fusion leads to telomere clustering to provide templates for homology-directed telomere synthesis, an ability that is decoupled from APB function in enriching DNA repair factors.

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Pharmacological targeting of differential DNA repair, radio-sensitizes WRN-deficient cancer cells in vitro and in vivo

Biochemical Pharmacology ◽

10.1016/j.bcp.2021.114450 ◽

2021 ◽

Vol 186 ◽

pp. 114450

Author(s):

Pooja Gupta ◽

Bhaskar Saha ◽

Subrata Chattopadhyay ◽

Birija Sankar Patro

Keyword(s):

Dna Repair ◽

Cancer Cells

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Platinum Complexes in Colorectal Cancer and Other Solid Tumors

Cancers ◽

10.3390/cancers13092073 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2073

Author(s):

Beate Köberle ◽

Sarah Schoch

Keyword(s):

Colorectal Cancer ◽

Dna Damage ◽

Dna Repair ◽

Cancer Cells ◽

Cisplatin Resistance ◽

Platinum Complexes ◽

Dna Lesions ◽

Dna Damage Signaling ◽

Repair Mechanisms ◽

P53 Inactivation

Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy.

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MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1903150116 ◽

2019 ◽

Vol 116 (35) ◽

pp. 17438-17443 ◽

Cited By ~ 6

Author(s):

Gayathri Srinivasan ◽

Elizabeth A. Williamson ◽

Kimi Kong ◽

Aruna S. Jaiswal ◽

Guangcun Huang ◽

...

Keyword(s):

Dna Repair ◽

Cancer Cells ◽

Synthetic Lethality ◽

Negative Regulator ◽

Nonhomologous End Joining ◽

Chromosomal Translocations ◽

Replication Forks ◽

Repair Pathway ◽

End Joining ◽

Parp1 Inhibitors

Defects in DNA repair give rise to genomic instability, leading to neoplasia. Cancer cells defective in one DNA repair pathway can become reliant on remaining repair pathways for survival and proliferation. This attribute of cancer cells can be exploited therapeutically, by inhibiting the remaining repair pathway, a process termed synthetic lethality. This process underlies the mechanism of the Poly-ADP ribose polymerase-1 (PARP1) inhibitors in clinical use, which target BRCA1 deficient cancers, which is indispensable for homologous recombination (HR) DNA repair. HR is the major repair pathway for stressed replication forks, but when BRCA1 is deficient, stressed forks are repaired by back-up pathways such as alternative nonhomologous end-joining (aNHEJ). Unlike HR, aNHEJ is nonconservative, and can mediate chromosomal translocations. In this study we have found that miR223-3p decreases expression of PARP1, CtIP, and Pso4, each of which are aNHEJ components. In most cells, high levels of microRNA (miR) 223–3p repress aNHEJ, decreasing the risk of chromosomal translocations. Deletion of the miR223 locus in mice increases PARP1 levels in hematopoietic cells and enhances their risk of unprovoked chromosomal translocations. We also discovered that cancer cells deficient in BRCA1 or its obligate partner BRCA1-Associated Protein-1 (BAP1) routinely repress miR223-3p to permit repair of stressed replication forks via aNHEJ. Reconstituting the expression of miR223-3p in BRCA1- and BAP1-deficient cancer cells results in reduced repair of stressed replication forks and synthetic lethality. Thus, miR223-3p is a negative regulator of the aNHEJ DNA repair and represents a therapeutic pathway for BRCA1- or BAP1-deficient cancers.

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