FANCD2-dependent mitotic DNA synthesis relies on PCNA K164 ubiquitination

Leung, Wendy; Baxley, Ryan M.; Traband, Emma; Chang, Ya-Chu; Rogers, Colette B.; Wang, Liangjun; Durrett, Wesley; Bromley, Kendall S.; Fiedorowicz, Lidia; Thakar, Tanay; Tella, Anika; Sobeck, Alexandra; Hendrickson, Eric A.; Moldovan, George-Lucian; Shima, Naoko; Bielinsky, Anja-Katrin

doi:10.1016/j.celrep.2023.113523

Cited by 4 publications

(4 citation statements)

References 44 publications

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“…PCNA K164 ubiquitination has recently been shown to participate in replication fork protection 36 and in preventing the accumulation of ssDNA gaps during DNA replication in unperturbed conditions 37 , two functions that have been previously also attributed to BRCA1 38 – 41 . Different groups have shown that BRCA1-deficient cancer cells accumulate ssDNA gaps and thus can be therapeutically exploited with PARP or REV1 inhibitors 39 , 42 .…”

Section: Resultsmentioning

confidence: 99%

BRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote continuous DNA synthesis

Salas-Lloret,

García-Rodríguez,

Soto-Hidalgo

et al. 2024

Nat Commun

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Deficiencies in the BRCA1 tumor suppressor gene are the main cause of hereditary breast and ovarian cancer. BRCA1 is involved in the Homologous Recombination DNA repair pathway and, together with BARD1, forms a heterodimer with ubiquitin E3 activity. The relevance of the BRCA1/BARD1 ubiquitin E3 activity for tumor suppression and DNA repair remains controversial. Here, we observe that the BRCA1/BARD1 ubiquitin E3 activity is not required for Homologous Recombination or resistance to Olaparib. Using TULIP2 methodology, which enables the direct identification of E3-specific ubiquitination substrates, we identify substrates for BRCA1/BARD1. We find that PCNA is ubiquitinated by BRCA1/BARD1 in unperturbed conditions independently of RAD18. PCNA ubiquitination by BRCA1/BARD1 avoids the formation of ssDNA gaps during DNA replication and promotes continuous DNA synthesis. These results provide additional insight about the importance of BRCA1/BARD1 E3 activity in Homologous Recombination.

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Section: Resultsmentioning

confidence: 99%

BRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote continuous DNA synthesis

Salas-Lloret,

García-Rodríguez,

Soto-Hidalgo

et al. 2024

Nat Commun

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“…DNA polymerase is important for cellular replication ( 21 ). PCNA expression is used as an indicator of cell proliferation due to its effects on mitotic activity ( 22 , 23 ). In this study, PCNA expression was also used as an indicator of cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicles isolated from curcumin-medium weakened RKO cell proliferation and migration

Xu,

Liu

2024

Transl Cancer Res

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Background Curcumin (Cur) is a natural phytochemical that is expected to become an indispensable drug for the treatment of colorectal cancer. A comprehensive understanding of the anti-tumor mechanism of Cur will provide a better reference for its clinical application. This study aimed to examine the effects of extracellular vesicles (EVs) isolated from Cur-medium on RKO colorectal cancer cell proliferation, apoptosis, and migration. Methods RKO cells were cultured in various concentrations of Cur-medium, and the EVs were isolated from the Cur-medium. The EVs were identified by transmission electron microscopy and western blotting. The effects of the EVs on RKO cell proliferation, apoptosis, and migration were analyzed, as was the expression of proliferating cell nuclear antigen (PCNA), Bax, vimentin, and E-cadherin. The expression of nuclear factor κB (NF-κB) p65 in the EVs was also detected. Results Our results showed that the EVs isolated from the Cur-medium weakened RKO cell proliferation and migration but had no effect on cell apoptosis. Cur suppressed the expression of NF-κB p65 in the EVs. Overall, this study revealed that Cur exerts anti-tumor effects by suppressing NF-κB p65 in EVs to weaken RKO cell proliferation and migration. Conclusions In conclusion, the packaging of Cur into EVs is expected to become an indispensable treatment of colorectal cancer in the future.

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“…In our study, the impact of the FANCD2 mutation on CML progression and drug resistance highlights the relationship between FANCD2 and the progression of CML to the advanced phase [ 17 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…There are several mechanisms involved in the initiation and progression of different types of cancers, including DNA repair defects leading to genomic instability [ 16 ]. Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by gene mutations that are predominantly involved in DNA damage response or repair [ 17 ]. The FANC genes play a crucial role in the FA pathway, regulating DNA damage responses through complicated processes like ubiquitination, phosphorylation, and degradation signals, all of which are required for genome stability and genomic integrity [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical Validation of the Somatic FANCD2 Mutation (c.2022-5C>T) as a Novel Molecular Biomarker for Early Disease Progression in Chronic Myeloid Leukemia: A Case–Control Study

Alanazi,

Siyal,

Basit

et al. 2024

Hematology Reports

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Background: Chronic myeloid leukemia (CML) results from chromosomal translocation t(9;22) leading to the formation of the BCR-ABL fusion oncogene. CML has three stages: the chronic phase (CP), the accelerated phase (AP), and the blast crisis (BC). Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML. TKIs work well in CP-CML, and these patients have a survival rate similar to the normal population, but TKIs are less effective in advanced-phase CML. Even with current advances in treatment, BC-CML patients have an average overall survival of less than a year. Early recognition of CML patients at risk of disease progression can help in timely interventions with appropriate TKIs or other therapeutic modalities. Although some markers of disease progression like BCR-ABL kinase domain, ASXL1, and GATA2 mutations are available, no universal and exclusively specific molecular biomarkers exist to early diagnose CML patients at risk of CML progression for timely therapeutic interventions to delay or minimize blast crisis transformation in CML. A recent study found that all BC-CML patients harbored the FANCD2 (c.2022-5C>T) mutation. Therefore, the current study was designed to detect this FANCD2 mutant in AP-CML (early progression phase) and to clinically validate its potential as a novel molecular biomarker of early CML progression from CP to AP. Methods: Our study comprised 123 CP-CML (control group) and 60 AP-CML patients (experimental group) from 2 oncology centers, from January 2020 to July 2023. Mean hemoglobin level, WBC count, platelet count, treatment type, hepatomegaly, splenomegaly, and survival status of AP-CML patients were significantly different from those of CP-CML patients. However, as these clinical parameters cannot help in the early detection of patients at risk of CML progression, there was a need for a clinically validated biomarker of AP-CML. DNA was extracted from the patients’ blood samples, and the FANCD2 gene was sequenced using an Illumina NextSeq500 next-generation sequencer (NGS). Results: The NGS analysis revealed a unique splice-site mutation in the FANCD2 gene (c.2022-5C>T). This mutation was detected in the majority (98.3%) of AP-CML patients but in none of the CP-CML patients or healthy control sequences from genomic databases. The mutation was confirmed by Sanger sequencing. FANCD2 is a member of the Fanconi anemia pathway genes involved in DNA repair and genomic stability, and aberrations of this gene are associated with many cancers. Conclusions: In conclusion, our study shows that the somatic FANCD2 (c.2022-5C>T) mutation is a new molecular biomarker for early CML progression. We recommend further clinical validation of this biomarker in prospective clinical trials.

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FANCD2-dependent mitotic DNA synthesis relies on PCNA K164 ubiquitination

Cited by 4 publications

References 44 publications

BRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote continuous DNA synthesis

BRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote continuous DNA synthesis

Extracellular vesicles isolated from curcumin-medium weakened RKO cell proliferation and migration

Clinical Validation of the Somatic FANCD2 Mutation (c.2022-5C>T) as a Novel Molecular Biomarker for Early Disease Progression in Chronic Myeloid Leukemia: A Case–Control Study

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