Abstract 2996: DNA-damaging agents disrupt telomere structure

DNA double-strand breaks (DSBs) are the most deleterious form of DNA damage and are repaired through non-homologous end-joining (NHEJ) or homologous recombination (HR). Repair initiation, regulation and communication with signaling pathways require several histone-modifying and chromatin-remodeling complexes. In budding yeast, this involves three primary complexes: INO80-C, which is primarily associated with HR, SWR1-C, which promotes NHEJ, and RSC-C, which is involved in both pathways as well as the general DNA damage response. Here we identify ARP6 as a factor involved in DSB repair through an RSC-C-related pathway. The loss of ARP6 significantly reduces the NHEJ repair efficiency of linearized plasmids with cohesive ends, impairs the repair of chromosomal breaks, and sensitizes cells to DNA-damaging agents. Genetic interaction analysis indicates that ARP6, MRE11 and RSC-C function within the same pathway, and the overexpression of ARP6 rescues rsc2∆ and mre11∆ sensitivity to DNA-damaging agents. Double mutants of ARP6, and members of the INO80 and SWR1 complexes, cause a significant reduction in repair efficiency, suggesting that ARP6 functions independently of SWR1-C and INO80-C. These findings support a novel role for ARP6 in DSB repair that is independent of the SWR1 chromatin remodeling complex, through an apparent RSC-C and MRE11-associated DNA repair pathway.

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Telomeric and Sub-Telomeric Structure and Implications in Fungal Opportunistic Pathogens

Microorganisms ◽

10.3390/microorganisms9071405 ◽

2021 ◽

Vol 9 (7) ◽

pp. 1405

Author(s):

Raffaella Diotti ◽

Michelle Esposito ◽

Chang Hui Shen

Keyword(s):

Fungal Pathogens ◽

Functional Abilities ◽

Opportunistic Pathogens ◽

Telomeric Sequences ◽

Coding Regions ◽

Telomeric Structure ◽

Linear Chromosomes ◽

Dna Ends ◽

Telomere Structure

Telomeres are long non-coding regions found at the ends of eukaryotic linear chromosomes. Although they have traditionally been associated with the protection of linear DNA ends to avoid gene losses during each round of DNA replication, recent studies have demonstrated that the role of these sequences and their adjacent regions go beyond just protecting chromosomal ends. Regions nearby to telomeric sequences have now been identified as having increased variability in the form of duplications and rearrangements that result in new functional abilities and biodiversity. Furthermore, unique fungal telomeric and chromatin structures have now extended clinical capabilities and understanding of pathogenicity levels. In this review, telomere structure, as well as functional implications, will be examined in opportunistic fungal pathogens, including Aspergillus fumigatus, Candida albicans, Candida glabrata, and Pneumocystis jirovecii.

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A stapled peptide mimetic of the CtIP tetramerization motif interferes with double-strand break repair and replication fork protection

Science Advances ◽

10.1126/sciadv.abc6381 ◽

2021 ◽

Vol 7 (8) ◽

pp. eabc6381

Author(s):

Anika Kuster ◽

Nour L. Mozaffari ◽

Oliver J. Wilkinson ◽

Jessica L. Wojtaszek ◽

Christina Zurfluh ◽

...

Keyword(s):

Strand Break ◽

Amino Acid Residues ◽

Dna Double Strand Breaks ◽

Strand Breaks ◽

Stapled Peptide ◽

Patients With Cancer ◽

Peptide Mimetic ◽

Dna Damaging Agents ◽

Stalled Replication Forks

Cancer cells display high levels of DNA damage and replication stress, vulnerabilities that could be exploited by drugs targeting DNA repair proteins. Human CtIP promotes homology-mediated repair of DNA double-strand breaks (DSBs) and protects stalled replication forks from nucleolytic degradation, thus representing an attractive candidate for targeted cancer therapy. Here, we establish a peptide mimetic of the CtIP tetramerization motif that inhibits CtIP activity. The hydrocarbon-stapled peptide encompassing amino acid residues 18 to 28 of CtIP (SP18–28) stably binds to CtIP tetramers in vitro and facilitates their aggregation into higher-order structures. Efficient intracellular uptake of SP18–28 abrogates CtIP localization to damaged chromatin, impairs DSB repair, and triggers extensive fork degradation. Moreover, prolonged SP18–28 treatment causes hypersensitivity to DNA-damaging agents and selectively reduces the viability of BRCA1-mutated cancer cell lines. Together, our data provide a basis for the future development of CtIP-targeting compounds with the potential to treat patients with cancer.

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The Power of Stress: The Telo-Hormesis Hypothesis

Cells ◽

10.3390/cells10051156 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1156

Author(s):

Maria Sol Jacome Burbano ◽

Eric Gilson

Keyword(s):

Stress Response ◽

Mutation Rates ◽

Basic Principles ◽

Beneficial Effects ◽

Response To Stress ◽

Telomere Biology ◽

Telomere Structure ◽

Structure And Functions

Adaptative response to stress is a strategy conserved across evolution to promote survival. In this context, the groundbreaking findings of Miroslav Radman on the adaptative value of changing mutation rates opened new avenues in our understanding of stress response. Inspired by this work, we explore here the putative beneficial effects of changing the ends of eukaryotic chromosomes, the telomeres, in response to stress. We first summarize basic principles in telomere biology and then describe how various types of stress can alter telomere structure and functions. Finally, we discuss the hypothesis of stress-induced telomere signaling with hormetic effects.

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Identification of the uvrD gene product of Escherichia coli as DNA helicase II and its induction by DNA-damaging agents.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)43445-4 ◽

1984 ◽

Vol 259 (3) ◽

pp. 1560-1565 ◽

Cited By ~ 10

Author(s):

K Kumura ◽

M Sekiguchi

Keyword(s):

Escherichia Coli ◽

Gene Product ◽

Dna Helicase ◽

Dna Helicase Ii ◽

Dna Damaging Agents

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Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes

Scientific Reports ◽

10.1038/s41598-020-63759-1 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Solene De Talhouet ◽

Julien Peron ◽

Aurelie Vuilleumier ◽

Alex Friedlaender ◽

Valeria Viassolo ◽

...

Keyword(s):

Breast Cancer ◽

Disease Free Survival ◽

Germline Mutations ◽

Brca1 And Brca2 ◽

Free Survival ◽

Entire Cohort ◽

Dna Damaging Agents ◽

Impact On Survival ◽

Brca1 Brca2 ◽

Brca1 And Brca2 Mutations

Abstract BRCA1/BRCA2 genes play a central role in DNA repair and their mutations increase sensitivity to DNA-damaging agents. There are conflicting data regarding the prognostic value of BRCA germline mutations in breast cancer (BC) patients. We collected clinical, pathological and genetic data of a cohort 925 BC patients preselected for genetic screening and treated with neoadjuvant or adjuvant chemotherapy, of whom 266 were BRCA carriers. Overall, 171 women carried a BRCA1 mutation, 95 carried a BRCA2 mutation, and 659 were non-carriers. In the entire cohort, there was a prolonged disease-free survival (DFS) for BRCA carriers (hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.44–0.90 for BRCA1; HR = 0.72; 95%CI, 0.47–1.1 for BRCA2; p = 0.020) and a trend toward prolonged disease-specific survival (DSS; HR = 0.65; 95%CI, 0.40–1.1 for BRCA1; HR = 0.78; 95%CI, 0.44–1.38 for BRCA2; p = 0.19) though not statistically significant. In the TNBC group, BRCA carriers had prolonged DFS (adjusted HR = 0.50; 95%CI, 0.28–0.89 for BRCA1; adjusted HR = 0.37; 95%CI, 0.11–1.25, for BRCA2; p = 0.034) and DSS (adjusted HR = 0.42; 95%CI, 0.21–0.82 for BRCA1; adjusted HR = 0.45; 95%CI, 0.11–1.9 for BRCA2; p = 0.023). In the non-TNBC group, the BRCA1 or BRCA2 mutations did not have any impact on survival. These results suggest that BRCA1/BRCA2 germline mutations are associated with prolonged survival only if women were diagnosed with TNBC.

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Archaeal RecA homologues: different response to DNA-damaging agents in mesophilic and thermophilic Archaea

Extremophiles ◽

10.1007/s007920100197 ◽

2001 ◽

Vol 5 (4) ◽

pp. 265-275 ◽

Cited By ~ 13

Author(s):

Claudia Reich ◽

Leslie McNeil ◽

Jennifer Brace ◽

Jacqueline Brucker ◽

Gary Olsen

Keyword(s):

Dna Damaging Agents ◽

Different Response ◽

Thermophilic Archaea

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p53-dependent and p53-independent activation of apoptosis in mammary epithelial cells reveals a survival function of EGF and insulin.

The Journal of Cell Biology ◽

10.1083/jcb.128.6.1185 ◽

1995 ◽

Vol 128 (6) ◽

pp. 1185-1196 ◽

Cited By ~ 114

Author(s):

G R Merlo ◽

F Basolo ◽

L Fiore ◽

L Duboc ◽

N E Hynes

Keyword(s):

Mammary Epithelial Cells ◽

P53 Protein ◽

Survival Function ◽

Mammary Epithelial ◽

Nuclear Accumulation ◽

Temperature Sensitive ◽

Dna Damaging Agents ◽

A Cells ◽

Hc11 Cells ◽

P53 Tumor Suppressor Protein

The p53 tumor suppressor protein has been implicated as a mediator of programmed cell death (PCD). A series of nontransformed mammary epithelial cell (MEC) lines were used to correlate p53 function with activation of PCD. Treatment of MECs expressing mutant, inactive, or no p53 with DNA-damaging agents did not induce apoptosis. Upon introduction of temperature-sensitive p53 into HC11 cells, which lack wild-type (wt) p53, PCD was observed after mitomycin treatment at 32 degrees, when the ts p53 protein is in wt conformation. Thus, wt p53 mediates activation of PCD in response to mitomycin in HC11 cells. Treatment of the MCF10-A cells, which express wt p53, with various DNA-damaging agents led to nuclear accumulation of p53. Only mitomycin treatment led to an increase in the number of apoptotic nuclei. ErbB-2-transformed MCF10-A cells responded to mitomycin, cisplatin, and 5-Fl-uracil, suggesting that signaling from activated ErbB-2 enhances the cells ability to respond to DNA damage. A combination of high cell density and serum-free medium induces apoptosis in all MECs tested, irrespective of their p53 status. Under these conditions, EGF or insulin act as survival factors in preventing PCD. These data might elucidate some aspects of breast involution and tumorigenesis.

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