The canine RAD51 mutation leads to the attenuation of interaction with PALB2

Uemura, Mitsuki; Ochiai, Kazuhiko; Morimatsu, Masami; Michishita, Masaki; Onozawa, Eri; Azakami, Daigo; Uno, Yumiko; Yoshikawa, Yasunaga; Sasaki, Takanori; Watanabe, Masami; Omi, Toshinori

doi:10.1111/vco.12542

Cited by 4 publications

(6 citation statements)

References 36 publications

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“… 23,24 The deleted Q × 10 mutant coupled with the VP16 transactivation domain co‐transfected with 4 ng of pNL1.1[Nluc] Nluc reporter plasmid (Promega) containing 4 × GAL4 upstream activating sequences and 2 ng of pGL4.51 plasmid (Promega) into the HeLa and MDCK cells, which were purchased from ATCC, showed a significantly strong interaction with the LBD coupled with the GAL4 DBD domain; this was contrasted with the activities of the Q × 10 control in the mammalian two‐hybrid assay (MTH) with 1 nM DHT stimulation (Figure 2B,C). 25 However, the Q × 9, 11, and 12 variants did not show significant differences in their interactions with LBD compared with the Q × 10 control. A single glutamine fluctuation in the polyQ region in canine AR N‐terminals may not decisively affect the interaction between NTD and LBD.…”

Section: Figurementioning

confidence: 82%

The number of glutamines in the N‐terminal of the canine androgen receptor affects signalling intensities

Ochiai

Sutijarit

Uemura

et al. 2020

Vet Comparative Oncology

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Most male dogs are castrated at young ages, making them easy to rear following androgen deprivation. Although the incidence of canine prostate cancer is low, several patients have resistance to androgen therapy and poor clinical prognosis. These outcomes are similar to those of end‐stage human androgen‐independent prostate cancer. The androgen receptor (AR) of canines has two polyglutamine (polyQ) sequences (Q × 10 and Q × 23) at its N‐terminal. The length of polyQ may be a risk factor for the development of prostate cancer in dogs; however, there is no evidence to support this. Hence, we artificially created polyQ deletion mutants of canine AR and evaluated their effects on AR signalling. The deletions of Q × 10 and Q × 23 were associated with significant reductions in AR signalling intensities. The Q × 10 mutants, which increase or decrease Q sequentially, also altered AR signalling. Furthermore, the Q × 10 deletion mutant, compared with the Q × 10 control, altered the intensities of the binding of polyQ to the C‐terminal of AR, which contains a ligand‐binding domain; this was not observed with the Q × 9, 11, and 12 variants. The number of glutamines in the N‐terminals of canine ARs may influence AR signalling intensities and contribute to the risk of prostate cancer in dogs.

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Section: Figurementioning

confidence: 82%

The number of glutamines in the N‐terminal of the canine androgen receptor affects signalling intensities

Ochiai

Sutijarit

Uemura

et al. 2020

Vet Comparative Oncology

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“…HR is essential for DNA double‐strand break repair and cancer prevention (Hodgson & Turashvili, 2020 ; O'kane et al., 2017 ; Trenner & Sartori, 2019 ). Studies have shown a relationship between mutations in the BRCA2 (Borge et al., 2011 ; Enginler et al., 2014 ; Kaszak et al., 2018 ; Lüder Ripoli et al., 2016 ; Ozmen et al., 2017a ) and RAD51 genes and CMT (Canadas et al., 2018 ; Ozmen et al., 2017b ; Uemura et al., 2019 ). The significance of PALB2 mutations in BCs is well known and is routinely monitored (Cock‐Rada et al., 2018 ; Schroeder et al., 2015 ; Slavin et al., 2015 ; Yao et al., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis of PALB2 gene WD40 domain in canine mammary tumour patients

Çıldır,

Özmen,

Kul

et al. 2024

Veterinary Medicine & Sci

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BackgroundDNA repair mechanisms are essential for tumorigenesis and disruption of HR mechanism is an important predisposing factor of human breast cancers (BC). PALB2 is an important part of the HR. There are similarities between canine mammary tumours (CMT) and BCs. As its human counterpart, PALB2 mutations could be a predisposing factor of CMT.ObjectivesIn this study, we aimed to investigate the impacts of PALB2 variants on tumorigenesis and canine mammary tumor (CMT) malignancy.MethodsWe performed Sanger sequencing to detect germline mutations in the WD40 domain of the canine PALB2 gene in CMT patients. We conducted in silico analysis to investigate the variants, and compared the germline PALB2 mutations in humans that cause breast cancer (BC) with the variants detected in dogs with CMT.ResultsWe identified an intronic (c.3096+8C>G) variant, two exonic (p.A1050V and p.R1354R) variants, and a 3′ UTR variant (c.4071T>C). Of these, p.R1354R and c.4071T>C novel variants were identified for the first time in this study. We found that the p.A1050V mutation had a significant effect. However, we could not determine sufficient similarity due to the differences in nucleotide/amino acid sequences between two species. Nonetheless, possible variants of human sequences in the exact location as their dog counterparts are associated with several cancer types, implying that the variants could be crucial for tumorigenesis in dogs. Our results did not show any effect of the variants on tumor malignancy.ConclusionsThe current project is the first study investigating the relationship between the PALB2 gene WD40 domain and CMTs. Our findings will contribute to a better understanding of the pathogenic mechanism of the PALB2 gene in CMTs. In humans, variant positions in canines have been linked to cancer‐related phenotypes such as familial BC, endometrial tumor, and hereditary cancer predisposition syndrome. The results of bioinformatics analyses should be investigated through functional tests or case‐control studies.

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“…A two‐hybrid assay indicated that the interaction of mutant type Rad51 with PALB2 was weaker than that of wild type Rad51. The conclusion was that RAD51 mutations affected oligomerization of the protein and that this could be the reason for its attenuated interaction with PALB2, which could promote cancer in dogs 49 …”

Section: Selected Ddr Proteins and Their Potential Role In Canine Res...mentioning

confidence: 99%

Section: Selected Ddr Proteins and Their Potential...mentioning

confidence: 99%

“…The conclusion was that RAD51 mutations affected oligomerization of the protein and that this could be the reason for its attenuated interaction with PALB2, which could promote cancer in dogs. 49 Ozmen et al investigated genetic variations in exons 11 and 27 of BRCA2 gene (a region corresponding to Rad51 binding site), and variations in exons 6 to 9 from RAD51 gene (corresponding to PALB2 and BRCA2 interaction regions) in canine mammary gland. The most prevalent polymorphism found was T1425P in BRC3.…”

Section: Rad51mentioning

confidence: 99%

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DNA damage response proteins in canine cancer as potential research targets in comparative oncology

Hernandez-Suarez

Gillespie

Pawlak

2022

Vet Comparative Oncology

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The DNA damage response (DDR) is a complex signal transduction network that is activated when endogenous or exogenous genotoxins damage or interfere with the replication of genomic DNA. Under such conditions, the DDR promotes DNA repair and ensures accurate replication and division of the genome. High levels of genomic instability are frequently observed in cancers and can stem from germline loss‐of‐function mutations in certain DDR genes, such as BRCA1, BRCA2, and p53, that form the basis of human cancer predisposition syndromes. In addition, mutation and/or aberrant expression of multiple DDR genes are frequently observed in sporadic human cancers. As a result, the DDR is considered to represent a viable target for cancer therapy in humans and a variety of strategies are under investigation. Cancer is also a significant cause of mortality in dogs, a species that offers certain advantages for experimental oncology. Domestic dogs present numerous inbred lines, many of which display predisposition to specific forms of cancer and the study of which may provide insight into the biological basis of this susceptibility. In addition, clinical trials are possible in dogs and may lead to therapeutic insights that could ultimately be extended to humans. Here we review what is known specifically about the DDR in dogs and discuss how this knowledge could be extended and exploited to advance experimental oncology in this species.

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The canine RAD51 mutation leads to the attenuation of interaction with PALB2

Cited by 4 publications

References 36 publications

The number of glutamines in the N‐terminal of the canine androgen receptor affects signalling intensities

The number of glutamines in the N‐terminal of the canine androgen receptor affects signalling intensities

Genetic analysis of PALB2 gene WD40 domain in canine mammary tumour patients

DNA damage response proteins in canine cancer as potential research targets in comparative oncology

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