scholarly journals PD-L1 upregulation is associated with activation of the DNA double-strand break repair pathway in patients with colitic cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Naoya Ozawa ◽  
Takehiko Yokobori ◽  
Katsuya Osone ◽  
Chika Katayama ◽  
Kunihiko Suga ◽  
...  
Keyword(s):  
Immune Cell ◽  
Strand Break ◽  
Double Strand Break ◽  
Chronic Inflammatory Disease ◽  
Sporadic Colorectal Cancer ◽  
Cancer Tissue ◽  
Repair Pathway ◽  
Dsb Repair ◽  
Dna Double Strand Break ◽  
Colitic Cancer

AbstractUlcerative colitis (UC) is a DNA damage-associated chronic inflammatory disease; the DNA double-strand break (DSB) repair pathway participates in UC-associated dysplasia/colitic cancer carcinogenesis. The DSB/interferon regulatory factor-1 (IRF-1) pathway can induce PD-L1 expression transcriptionally. However, the association of PD-L1/DSB/IRF-1 with sporadic colorectal cancer (SCRC), and UC-associated dysplasia/colitic cancer, remains elusive. Therefore, we investigated the significance of the PD-L1/DSB repair pathway using samples from 17 SCRC and 12 UC patients with rare UC-associated dysplasia/colitic cancer cases by immunohistochemical analysis. We compared PD-L1 expression between patients with SCRC and UC-associated dysplasia/colitic cancer and determined the association between PD-L1 and the CD8+ T-cell/DSB/IRF-1 axis in UC-associated dysplasia/colitic cancer. PD-L1 expression in UC and UC-associated dysplasia/colitic cancer was higher than in normal mucosa or SCRC, and in CD8-positive T lymphocytes in UC-associated dysplasia/colitic cancer than in SCRC. Moreover, PD-L1 upregulation was associated with γH2AX (DSB marker) and IRF-1 upregulation in UC-associated dysplasia/colitic cancer. IRF-1 upregulation was associated with γH2AX upregulation in UC-associated dysplasia/colitic cancer but not in SCRC. Multicolour immunofluorescence staining validated γH2AX/IRF-1/PD-L1 co-expression in colitic cancer tissue sections. Thus, immune cell-induced inflammation might activate the DSB/IRF-1 axis, potentially serving as the primary regulatory mechanism of PD-L1 expression in UC-associated carcinogenesis.

PD-L1 upregulation is associated with activation of the DNA double-strand break repair pathway in patients with colitic cancer

2021 ◽  
Author(s):  
Naoya Ozawa ◽  
Takehiko Yokobori ◽  
Katsuya Osone ◽  
Chika Katayama ◽  
Kunihiko Suga ◽  
...  
Keyword(s):  
Immune Cell ◽  
Strand Break ◽  
Double Strand Break ◽  
Chronic Inflammatory Disease ◽  
Sporadic Colorectal Cancer ◽  
Cancer Tissue ◽  
Repair Pathway ◽  
Dsb Repair ◽  
Dna Double Strand Break ◽  
Colitic Cancer

Abstract Ulcerative colitis (UC) is a DNA damage-associated chronic inflammatory disease; the DNA double-strand break (DSB) repair pathway participates in UC-associated dysplasia/colitic cancer carcinogenesis. The DSB/interferon regulatory factor-1 (IRF-1) pathway can induce PD-L1 expression transcriptionally. However, the association of PD-L1/DSB/IRF-1 with sporadic colorectal cancer (SCRC), and UC-associated dysplasia/colitic cancer, remains elusive. Therefore, we investigated the significance of the PD-L1/DSB repair pathway using samples from 17 SCRC and 12 UC patients with rare UC-associated dysplasia/colitic cancer cases by immunohistochemical analysis. We compared PD-L1 expression between patients with SCRC and UC-associated dysplasia/colitic cancer and determined the association between PD-L1 and the CD8+ T-cell/DSB/IRF-1 axis in UC-associated dysplasia/colitic cancer. PD-L1 expression in UC and UC-associated dysplasia/colitic cancer was higher than in normal mucosa or SCRC, and in CD8-positive T lymphocytes in UC-associated dysplasia/colitic cancer than in SCRC. Moreover, PD-L1 upregulation was associated with γH2AX (DSB marker) and IRF-1 upregulation in UC-associated dysplasia/colitic cancer. IRF-1 upregulation was associated with γH2AX upregulation in UC-associated dysplasia/colitic cancer but not in SCRC. Multicolour immunofluorescence staining validated γH2AX/IRF-1/PD-L1 co-expression in colitic cancer tissue sections. Thus, immune cell-induced inflammation might activate the DSB/IRF-1 axis, potentially serving as the primary regulatory mechanism of PD-L1 expression in UC-associated carcinogenesis.

Impact of chromatin context on Cas9-induced DNA double-strand break repair pathway balance

2020 ◽  
Author(s):  
Ruben Schep ◽  
Eva K. Brinkman ◽  
Christ Leemans ◽  
Xabier Vergara ◽  
Ben Morris ◽  
...  
Keyword(s):  
Genome Editing ◽  
Strand Break ◽  
Double Strand Break ◽  
Repair Pathway ◽  
End Joining ◽  
Dsb Repair ◽  
Dna Double Strand Break ◽  
Repair Pathways ◽  
Non Homologous End Joining ◽  
The Impact

AbstractDNA double-strand break (DSB) repair is mediated by multiple pathways, including classical non-homologous end-joining pathway (NHEJ) and several homology-driven repair pathways. This is particularly important for Cas9-mediated genome editing, where the outcome critically depends on the pathway that repairs the break. It is thought that the local chromatin context affects the pathway choice, but the underlying principles are poorly understood. Using a newly developed multiplexed reporter assay in combination with Cas9 cutting, we systematically measured the relative activities of three DSB repair pathways as function of chromatin context in >1,000 genomic locations. This revealed that NHEJ is broadly biased towards euchromatin, while microhomology-mediated end-joining (MMEJ) is more efficient in specific heterochromatin contexts. In H3K27me3-marked heterochromatin, inhibition of the H3K27 methyltransferase EZH2 shifts the balance towards NHEJ. Single-strand templated repair (SSTR), often used for precise CRISPR editing, competes with MMEJ, and this competition is weakly associated with chromatin context. These results provide insight into the impact of chromatin on DSB repair pathway balance, and guidance for the design of Cas9-mediated genome editing experiments.

scholarly journals Phosphorylation of Ku dictates DNA double-strand break (DSB) repair pathway choice in S phase

2015 ◽  
Vol 44 (4) ◽  
pp. 1732-1745 ◽  
Author(s):  
Kyung-Jong Lee ◽  
Janapriya Saha ◽  
Jingxin Sun ◽  
Kazi R. Fattah ◽  
Shu-Chi Wang ◽  
...  
Keyword(s):  
Strand Break ◽  
Double Strand Break ◽  
S Phase ◽  
Repair Pathway ◽  
Dsb Repair ◽  
Dna Double Strand Break ◽  
Pathway Choice

scholarly journals Impact of chromatin context on Cas9-induced DNA double-strand break repair pathway balance

2021 ◽  
Author(s):  
Ruben Schep ◽  
Eva K. Brinkman ◽  
Christ Leemans ◽  
Xabier Vergara ◽  
Robin H. van der Weide ◽  
...  
Keyword(s):  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Repair Pathway ◽  
Dna Double Strand Break ◽  
Break Repair

scholarly journals BRCA-related ATM-mediated DNA double-strand break repair and ovarian aging

2019 ◽  
Vol 26 (1) ◽  
pp. 43-57 ◽  
Author(s):  
Volkan Turan ◽  
Kutluk Oktay
Keyword(s):  
Clinical Evidence ◽  
Strand Break ◽  
Oocyte Quality ◽  
Repair Pathway ◽  
Dsb Repair ◽  
Ovarian Aging ◽  
Age Related ◽  
Dna Double Strand Break ◽  
Targeted Treatments ◽  
Oocyte Aging

Abstract BACKGROUND Oocyte aging has significant clinical consequences, and yet no treatment exists to address the age-related decline in oocyte quality. The lack of progress in the treatment of oocyte aging is due to the fact that the underlying molecular mechanisms are not sufficiently understood. BRCA1 and 2 are involved in homologous DNA recombination and play essential roles in ataxia telangiectasia mutated (ATM)-mediated DNA double-strand break (DSB) repair. A growing body of laboratory, translational and clinical evidence has emerged within the past decade indicating a role for BRCA function and ATM-mediated DNA DSB repair in ovarian aging. OBJECTIVE AND RATIONALE Although there are several competing or complementary theories, given the growing evidence tying BRCA function and ATM-mediated DNA DSB repair mechanisms in general to ovarian aging, we performed this review encompassing basic, translational and clinical work to assess the current state of knowledge on the topic. A clear understanding of the mechanisms underlying oocyte aging may result in targeted treatments to preserve ovarian reserve and improve oocyte quality. SEARCH METHODS We searched for published articles in the PubMed database containing key words, BRCA, BRCA1, BRCA2, Mutations, Fertility, Ovarian Reserve, Infertility, Mechanisms of Ovarian Aging, Oocyte or Oocyte DNA Repair, in the English-language literature until May 2019. We did not include abstracts or conference proceedings, with the exception of our own. OUTCOMES Laboratory studies provided robust and reproducible evidence that BRCA1 function and ATM-mediated DNA DSB repair, in general, weakens with age in oocytes of multiple species including human. In both women with BRCA mutations and BRCA-mutant mice, primordial follicle numbers are reduced and there is accelerated accumulation of DNA DSBs in oocytes. In general, women with BRCA1 mutations have lower ovarian reserves and experience earlier menopause. Laboratory evidence also supports critical role for BRCA1 and other ATM-mediated DNA DSB repair pathway members in meiotic function. When laboratory, translational and clinical evidence is considered together, BRCA-related ATM-mediated DNA DSB repair function emerges as a likely regulator of ovarian aging. Moreover, DNA damage and repair appear to be key features in chemotherapy-induced ovarian aging. WIDER IMPLICATIONS The existing data suggest that the BRCA-related ATM-mediated DNA repair pathway is a strong candidate to be a regulator of oocyte aging, and the age-related decline of this pathway likely impairs oocyte health. This knowledge may create an opportunity to develop targeted treatments to reverse or prevent physiological or chemotherapy-induced oocyte aging. On the immediate practical side, women with BRCA or similar mutations may need to be specially counselled for fertility preservation.

scholarly journals Clustered DNA double-strand break formation and the repair pathway following heavy-ion irradiation

2018 ◽  
Vol 60 (1) ◽  
pp. 69-79 ◽  
Author(s):  
Yoshihiko Hagiwara ◽  
Takahiro Oike ◽  
Atsuko Niimi ◽  
Motohiro Yamauchi ◽  
Hiro Sato ◽  
...  
Keyword(s):  
Ion Irradiation ◽  
Heavy Ion ◽  
Strand Break ◽  
Double Strand Break ◽  
Repair Pathway ◽  
Heavy Ion Irradiation ◽  
Dna Double Strand Break ◽  
Break Formation

scholarly journals A histone H3K36 chromatin switch coordinates DNA double-strand break repair pathway choice

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Chen-Chun Pai ◽  
Rachel S. Deegan ◽  
Lakxmi Subramanian ◽  
Csenge Gal ◽  
Sovan Sarkar ◽  
...  
Keyword(s):  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Repair Pathway ◽  
Dna Double Strand Break ◽  
Pathway Choice ◽  
Break Repair

scholarly journals SHLD 2/ FAM 35A co‐operates with REV 7 to coordinate DNA double‐strand break repair pathway choice

2018 ◽  
Vol 37 (18) ◽  
Author(s):  
Steven Findlay ◽  
John Heath ◽  
Vincent M Luo ◽  
Abba Malina ◽  
Théo Morin ◽  
...  
Keyword(s):  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Repair Pathway ◽  
Dna Double Strand Break ◽  
Pathway Choice ◽  
Break Repair

scholarly journals The Roles of Bacterial DNA Double-Strand Break Repair Proteins in Chromosomal DNA Replication

2020 ◽  
Vol 44 (3) ◽  
pp. 351-368 ◽  
Author(s):  
Anurag Kumar Sinha ◽  
Christophe Possoz ◽  
David R F Leach
Keyword(s):  
Dna Replication ◽  
Cell Viability ◽  
Strand Break ◽  
Double Strand Break ◽  
Replication Initiation ◽  
Genome Replication ◽  
Chromosomal Dna ◽  
Dsb Repair ◽  
Bacterial Dna ◽  
Dna Double Strand Break

ABSTRACT It is well established that DNA double-strand break (DSB) repair is required to underpin chromosomal DNA replication. Because DNA replication forks are prone to breakage, faithful DSB repair and correct replication fork restart are critically important. Cells, where the proteins required for DSB repair are absent or altered, display characteristic disturbances to genome replication. In this review, we analyze how bacterial DNA replication is perturbed in DSB repair mutant strains and explore the consequences of these perturbations for bacterial chromosome segregation and cell viability. Importantly, we look at how DNA replication and DSB repair processes are implicated in the striking recent observations of DNA amplification and DNA loss in the chromosome terminus of various mutant Escherichia coli strains. We also address the mutant conditions required for the remarkable ability to copy the entire E. coli genome, and to maintain cell viability, even in the absence of replication initiation from oriC, the unique origin of DNA replication in wild type cells. Furthermore, we discuss the models that have been proposed to explain these phenomena and assess how these models fit with the observed data, provide new insights and enhance our understanding of chromosomal replication and termination in bacteria.

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