Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1

Hernández, Gonzalo; Ramı́rez, Marı́a José; Minguillón, Jordi; Quiles, Paco; Garibay, Gorka Ruíz de; Aza‐Carmona, Miriam; Bogliolo, Massimo; Pujol, Roser; Prados-Carvajal, Rosario; Fernández, José María Pérez; García, Nadia; López, Adrià; Gutiérrez‐Enríquez, Sara; Dı́ez, Orland; Benı́tez, Javier; Salinas, Mónica; Teulé, Àlex; Brunet, Joan; Radice, Paolo; Peterlongo, Paolo; Schindler, Detlev; Huertas, Pablo; Puente, Xosé S.; Lázaro, Conxi; Pujana, Miquel Àngel; Surrallés, Jordi

doi:10.1038/s41467-018-03433-3

Cited by 34 publications

(24 citation statements)

References 44 publications

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“…Indeed, Pearl et al [19] have documented complex functional impairment in DDR in several cancer types. Importance of DNA repair pathways (a constituent part of DDR) in maintaining genomic instability and cancer etiology is highlighted in familial cancers with known high-penetrance germline mutations in DNA repair genes: BRCA1/BRCA2 in breast cancer, MMR and polymerase deficiency (MLH1, MSH2, MSH6, PMS2 and POLE genes) in CRC and ovarian cancers, deleterious mutations in RAD51C and RAD51D and BRCA1 mutation in ovarian cancers [20][21][22][23][24][25][26].…”

Section: Dna Damage and Colorectal Cancer Pathogenesismentioning

confidence: 99%

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients

Vodička

Urbanová

Makovický

et al. 2020

IJMS

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Oxidative stress with subsequent premutagenic oxidative DNA damage has been implicated in colorectal carcinogenesis. The repair of oxidative DNA damage is initiated by lesion-specific DNA glycosylases (hOGG1, NTH1, MUTYH). The direct evidence of the role of oxidative DNA damage and its repair is proven by hereditary syndromes (MUTYH-associated polyposis, NTHL1-associated tumor syndrome), where germline mutations cause loss-of-function in glycosylases of base excision repair, thus enabling the accumulation of oxidative DNA damage and leading to the adenoma-colorectal cancer transition. Unrepaired oxidative DNA damage often results in G:C>T:A mutations in tumor suppressor genes and proto-oncogenes and widespread occurrence of chromosomal copy-neutral loss of heterozygosity. However, the situation is more complicated in complex and heterogeneous disease, such as sporadic colorectal cancer. Here we summarized our current knowledge of the role of oxidative DNA damage and its repair on the onset, prognosis and treatment of sporadic colorectal cancer. Molecular and histological tumor heterogeneity was considered. Our study has also suggested an additional important source of oxidative DNA damage due to intestinal dysbiosis. The roles of base excision repair glycosylases (hOGG1, MUTYH) in tumor and adjacent mucosa tissues of colorectal cancer patients, particularly in the interplay with other factors (especially microenvironment), deserve further attention. Base excision repair characteristics determined in colorectal cancer tissues reflect, rather, a disease prognosis. Finally, we discuss the role of DNA repair in the treatment of colon cancer, since acquired or inherited defects in DNA repair pathways can be effectively used in therapy.

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Section: Dna Damage and Colorectal Cancer Pathogenesismentioning

confidence: 99%

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients

Vodička

Urbanová

Makovický

et al. 2020

IJMS

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“…EDC4 interacts with BRCA1, a tumor suppressor that regulates DNA repair by HR, and promotes end resection through a mechanism that is independent of its role in mRNA decapping. [ 47 ] The RNA exosome is also rapidly recruited to DSBs through a mechanism that requires the DNA:RNA helicase Senataxin (SETX). [ 48,49 ] Cells depleted of Exosome Component 10 (EXOSC10), one of the catalytic subunits of the exosome, show increased levels of dilncRNAs produced at sequence‐specific DSBs, which suggests that EXOSC10 is involved in the degradation of damage‐induced transcripts.…”

Section: Processing and Degradation Of Dilncrnasmentioning

confidence: 99%

RNA at DNA Double‐Strand Breaks: The Challenge of Dealing with DNA:RNA Hybrids

2020

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RNA polymerase II is recruited to DNA double-strand breaks (DSBs), transcribes the sequences that flank the break and produces a novel RNA type that has been termed damage-induced long non-coding RNA (dilncRNA). DilncRNAs can be processed into short, miRNA-like molecules or degraded by different ribonucleases. They can also form double-stranded RNAs or DNA:RNA hybrids. The DNA:RNA hybrids formed at DSBs contribute to the recruitment of repair factors during the early steps of homologous recombination (HR) and, in this way, contribute to the accuracy of the DNA repair. However, if not resolved, the DNA:RNA hybrids are highly mutagenic and prevent the recruitment of later HR factors. Here recent discoveries about the synthesis, processing, and degradation of dilncRNAs are revised. The focus is on RNA clearance, a necessary step for the successful repair of DSBs and the aim is to reconcile contradictory findings on the effects of dilncRNAs and DNA:RNA hybrids in HR.

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“…Western blot 2 × 10 5 cells were seeded on 6 well plates, 24 h later were treated with hydroxyurea, MMC or left untreated, and 24 h later cells were lyzed and SDS-PAGE and blotting with indicated antibodies performed as previously described [31].…”

Section: Survival Assaymentioning

confidence: 99%

High content drug screening for Fanconi anemia therapeutics

Montanuy

Camps-Fajol

Carreras‐Puigvert

et al. 2020

Orphanet J Rare Dis

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Background: Fanconi anemia is a rare disease clinically characterized by malformations, bone marrow failure and an increased risk of solid tumors and hematologic malignancies. The only therapies available are hematopoietic stem cell transplantation for bone marrow failure or leukemia, and surgical resection for solid tumors. Therefore, there is still an urgent need for new therapeutic options. With this aim, we developed a novel high-content cellbased screening assay to identify drugs with therapeutic potential in FA. Results: A TALEN-mediated FANCA-deficient U2OS cell line was stably transfected with YFP-FANCD2 fusion protein. These cells were unable to form fluorescent foci or to monoubiquitinate endogenous or exogenous FANCD2 upon DNA damage and were more sensitive to mitomycin C when compared to the parental wild type counterpart. FANCA correction by retroviral infection restored the cell line's ability to form FANCD2 foci and ubiquitinate FANCD2. The feasibility of this cell-based system was interrogated in a high content screening of 3802 compounds, including a Prestwick library of 1200 FDA-approved drugs. The potential hits identified were then individually tested for their ability to rescue FANCD2 foci and monoubiquitination, and chromosomal stability in the absence of FANCA. Conclusions: While, unfortunately, none of the compounds tested were able to restore cellular FANCA-deficiency, our study shows the potential capacity to screen large compound libraries in the context of Fanconi anemia therapeutics in an optimized and cost-effective platform.

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Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1

Cited by 34 publications

References 44 publications

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients

RNA at DNA Double‐Strand Breaks: The Challenge of Dealing with DNA:RNA Hybrids

High content drug screening for Fanconi anemia therapeutics

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