NEIL3 contributes to the Fanconi anemia/BRCA pathway by promoting the downstream double-strand break repair step

Li, Niu; Xu, Yan; Chen, Hongzhu; Chen, Lina; Zhang, Yi; Yu, Tao; Yao, Rutao; Chen, Jing; Fu, Qin; Zhou, Jia; Wang, Jian

doi:10.1016/j.celrep.2022.111600

Cited by 6 publications

(4 citation statements)

References 59 publications

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“…In addition, these proteins rely upon their abilities to bind single-strand/duplex DNA junctions at the replication fork. The DNA-binding properties of NEIL3 and HMCES, even in the absence of their catalytic activities, appear to enable roles in DNA repair that are separate from those described here. , …”

Section: Discussionmentioning

confidence: 73%

“…The DNA-binding properties of NEIL3 and HMCES, even in the absence of their catalytic activities, appear to enable roles in DNA repair that are separate from those described here. 97,98 It seems likely that future studies will reveal new roles for NEIL3 and HMCES in DNA repair, maintenance of genome stability, and the regulation of gene expression. In addition, we anticipate that additional substrates for the TRAIP-NEIL3 replication-dependent repair pathway will be identified.…”

Section: ■ Conclusionmentioning

confidence: 99%

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Novel Processes Associated with the Repair of Interstrand Cross-Links Derived from Abasic Sites in Duplex DNA: Roles for the Base Excision Repair Glycosylase NEIL3 and the SRAP Protein HMCES

Price,

Gates

2024

Chem. Res. Toxicol.

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Recent studies have defined a novel pathway for the repair of interstrand cross-links derived from the reaction of an adenine residue with an apurinic/apyrimidinic (AP) site on the opposing strand of DNA (dA-AP ICL). Stalling of a replication fork at the dA-AP ICL triggers TRAIP-dependent ubiquitylation of the CMG helicase that recruits the base excision repair glycosylase NEIL3 to the lesion. NEIL3 unhooks the dA-AP ICL to regenerate the native adenine residue on one strand and an AP site on the other strand. Covalent capture of the abasic site by the SRAP protein HMCES protects against genomic instability that would result from cleavage of the abasic site in the context of singlestranded DNA at the replication fork. After repair synthesis moves the HMCES-AP adduct into the context of double-stranded DNA, the DNA−protein cross-link is resolved by a nonproteolytic mechanism involving dissociation of thiazolidine attachment. The AP site in duplex DNA is then repaired by the base excision repair pathway.

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Section: Discussionmentioning

confidence: 73%

Section: ■ Conclusionmentioning

confidence: 99%

Novel Processes Associated with the Repair of Interstrand Cross-Links Derived from Abasic Sites in Duplex DNA: Roles for the Base Excision Repair Glycosylase NEIL3 and the SRAP Protein HMCES

Price,

Gates

2024

Chem. Res. Toxicol.

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“…[3,4] FANCL is just one of the FA complementation (FANC) genes, which include a total of 22 genes, namely FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN, FANCO, FANCP, FANCQ, FANCR, FANCS, FANCT, FANCU, FANCV, and FANCW. [5][6][7] Researches have reported that heterozygous mutations in the FANC genes may lead to an increased susceptibility to tumors and acquired BMF. [8][9][10][11] However, there is currently no literature reporting the relationship between FANCL heterozygous mutation and the onset of acquired BMF.…”

Section: Introductionmentioning

confidence: 99%

An acquired BMF with FANCL gene heterozygous mutation: Case report

Zhang¹,

Xiao²,

Miao³

et al. 2023

Medicine

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Rationale: Bone marrow failure (BMF) includes inherited and acquired BMFs. Acquired BMF can be secondary to various factors, such as autoimmune dysfunction, benzene, drugs, radiation, viral infection and so on. Fanconi anemia (FA) complementation group L (FANCL) is an E3 ubiquitin ligase that participates in the repair of DNA damage. Homozygous or compound heterozygous mutations of FANCL can lead to the onset of FA, which is one of the most common inherited BMFs.Patient concerns and Diagnoses: Here, we report a case of acquired BMF. This patient had a history of benzene exposure for half a year before the onset of the disease, and presented with progressive pancytopenia, especially the reduction of erythrocytes and megakaryocyte, without malformation. Interestingly, this patient and his brother/father had a heterozygous (non-homozygous/compound heterozygous) mutation (Exon9, c.745C > T, p.H249Y) in the FANCL gene. Interventions and Outcomes:The patient successfully underwent unrelated and fully compatible umbilical cord blood hematopoietic stem cell transplantation.Lessons subsections: We report for the first time an acquired BMF case with FANCL gene heterozygous mutation, and the mutation site (Exon9, c.745C > T, p.H249Y) has never been reported. This case suggests that heterozygous mutations in FANCL gene may be associated with increased susceptibility to acquired BMF. Based on current reports and this case, we speculate that heterozygous mutations in the FA complementation gene may exist in a certain proportion of tumor and acquired BMF patients, but have not been detected. We recommend routine screening for FA complementation gene mutations in tumor and acquired BMF patients in clinical practice. If positive results are found, further screening can be conducted on their families.

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“…MMC is a member of the alkyl family and can generate interstrand crosslinks (ICLs) between DNA duplexes, hence inhibiting DNA replication, leading to cell death [10]. However, cancer cells can remove ICLs via Fanconi anemia (FA) [11,12], translesion synthesis (TLS) [13,14], and homologous recombination repair pathway (HR) [15], etc., thereby generating drug resistance [16]. FA family proteins can recognize ICLs and "unhook" on one side of the DNA chain, leaving huge adducts on the opposite.…”

Section: Introductionmentioning

confidence: 99%

Rev1-Rev7 Complex Inhibitor JH-RE-06 Enhances Mitomycin C Chemosensitivity in HCT116 Colorectal Cancer Cells

Cheng

Sun

et al. 2023

Preprint

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Background: Cancer cells can develop resistance to DNA interstrand crosslinker agents through a DNA repair bypass pathway called TLS. JH-RE-06, a TLS-targeting inhibitor, has been shown to increase melanoma cell susceptibility to cisplatin. Nevertheless, whether JH-RE-06 can be used in combination with Mitomycin C (MMC) to benefit Colorectal Cancer (CRC) patients receiving hyperthermic intraperitoneal chemotherapy (HIPEC) treatment remains unknown. Methods: Colon adenocarcinoma (COAD) and Rectum adenocarcinoma (READ) data were obtained from The Cancer Genome Atlas (TCGA) database, and the expression of Rev1-associated proteins in normal and malignant tissues were compared to generate receiver operating characteristic curves (ROC) . The association between Rev1 and Rev7 expression and the prognosis of CRC patients was derived from the PrognoScan database. Expression at the protein level was verified with a tissue microarray. Western blot was performed to identify alterations in the protein levels of Rev1 and Rev7 following MMC treatment of HCT116 cells, whereas CCK8 revealed alterations in the IC50 value of MMC following the knockdown of Rev7 and Rev1. Co-Immunoprecipitation for the targeting of JH-RE-06. EdU demonstrated the inhibitory effect of JH-RE-06 and MMC on cancer cell growth; Wound healing, and clone formation assays were carried out to evaluate the cell migration and clone formation abilities, respectively. Flow cytometry analysis was performed to detect cell apoptosis, and a commercial reagent kit was used to detect ROS and NAD+/NADH changes. Immunofluorescence was used to analyze cellular DNA damage. Finally, the potential mechanism of action and targets of JH-RE-06 in the treatment of CRC were investigated by network pharmacology. Results: Analysis of bioinformatics data revealed high expression of Rev1 and Rev1-associated proteins Rad18, Rev3, and Rev7 in CRC tumor tissues compared to normal tissues, with Rad18 and Rev7 showing high diagnostic values for CRC. High Rev1 expression was associated with a poor prognosis, whereas high Rev7 expression was associated with a favorable prognosis. The protein-level expression of Rev1 and Rev7 was verified by immunohistochemistry, indicating that the downregulation of Rev1 and Rev7 may increase HCT116 susceptibility to MMC treatment. Co-treatment with JH-RE-06 may augment the therapeutic efficacy of MMC in CRC cells, increase cell apoptosis, mitochondrial and DNA damage, and limit cancer cell migration and clone formation. Results from network pharmacology revealed that JH-RE-06 treatment may also involve the MAPK, PI3K, and Akt signaling pathways. Conclusions: Rad18 and Rev7 can be employed as predictive biomarkers for CRC. Targeting TLS renders HCT116 sensitive to MMC treatment, and JH-RE-06 has the potential to serve as a combination therapy medication for the MMC treatment of peritoneal metastatic CRC in HIPEC.

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NEIL3 contributes to the Fanconi anemia/BRCA pathway by promoting the downstream double-strand break repair step

Cited by 6 publications

References 59 publications

Novel Processes Associated with the Repair of Interstrand Cross-Links Derived from Abasic Sites in Duplex DNA: Roles for the Base Excision Repair Glycosylase NEIL3 and the SRAP Protein HMCES

Novel Processes Associated with the Repair of Interstrand Cross-Links Derived from Abasic Sites in Duplex DNA: Roles for the Base Excision Repair Glycosylase NEIL3 and the SRAP Protein HMCES

An acquired BMF with FANCL gene heterozygous mutation: Case report

Rev1-Rev7 Complex Inhibitor JH-RE-06 Enhances Mitomycin C Chemosensitivity in HCT116 Colorectal Cancer Cells

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