The importance of making ends meet: Mutations in genes and altered expression of proteins of the MRN complex and cancer

Dzikiewicz‐Krawczyk, Agnieszka

doi:10.1016/j.mrrev.2008.05.005

Cited by 46 publications

(41 citation statements)

References 93 publications

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“…Moreover, epidemiologic studies have indicated that a reduced expression of NBS1 is observed in up to 80% of breast cancer cases without any reported mutations (45,46). Consistent with this, present results showed a reduced ubiquitination of g-tubulin in three cell lines from patients with NBS and in one human cancer cell line, LoVo, expressing low levels of NBS1 (Fig.…”

Section: Discussionsupporting

confidence: 91%

Inactivation of the Nijmegen Breakage Syndrome Gene Leads to Excess Centrosome Duplication via the ATR/BRCA1 Pathway

et al. 2009

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Nijmegen breakage syndrome is characterized by genomic instability and a predisposition for lymphoma and solid tumors. Nijmegen breakage syndrome 1 (NBS1), the protein which is mutated in these patients, functions in association with BRCA1 and ATR as part of the cellular response to DNA double-strand breaks. We show here that NBS1 forms foci at the centrosomes via an interaction with ;-tubulin. Down-regulation of NBS1 by small interfering RNA induces supernumerary centrosomes, and this was confirmed with experiments using Nbs1 knockout mouse cells; the introduction of wild-type NBS1 (wt-NBS1) cDNA into these knockout mouse cells reduced the number of supernumerary centrosomes to normal levels. This phenotype in NBS1-deficient cells is caused by both centrosome duplication and impaired separation of centrioles, which have been observed in BRCA1-inhibited cells. In fact, supernumerary centrosomes were observed in Brca1 knockout mouse cells, and the frequency was not affected by NBS1 down-regulation, suggesting that NBS1 maintains centrosomes via a common pathway with BRCA1. This is consistent with findings that NBS1 physically interacts with BRCA1 at the centrosomes and is required for BRCA1-mediated ubiquitination of ;-tubulin. Moreover, the ubiquitination of ;-tubulin is compromised by either ATR depletion or an NBS1 mutation in the ATR interacting (FHA) domain, which is essential for ATR activation. These results suggest that, although centrosomes lack DNA, the NBS1/ATR/ BRCA1 repair machinery affects centrosome behavior, and this might be a crucial role in the prevention of malignances.

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Section: Discussionsupporting

confidence: 91%

Inactivation of the Nijmegen Breakage Syndrome Gene Leads to Excess Centrosome Duplication via the ATR/BRCA1 Pathway

et al. 2009

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“…At least two explanations are proposed to explain why some amino acids are mutated more frequently than the others, namely, the "hotspot" sites sensitive to endogenous and exogenous mutagens [22,23], and the disruption of protein functions dependent upon the mutation position in a protein [24,25]. However, the mutation patterns based on them are difficult to model, which loses the meaning of generalization.…”

Section: Discussionmentioning

confidence: 99%

Mutation Patterns in Human Menin

Yan

Wu²

2009

2009 3rd International Conference on Bioinformatics and Biomedical Engineering

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The menin is a tumour suppressor protein, whose deficiency is the cause of familial multiple endocrine neoplasia type I (MEN1). To understand its mutation pattern is very helpful for managing its clinical manifest and outcome. The amino-acid pair predictability is used to transfer the symbolized human menin and its 99 missense point mutants to scalar data and classify the amino-acid pairs as predictable and unpredictable, in order to analyse the mutation pattern. The majority (81.81%) of substituted pairs are characterized by one or both pairs whose actual frequency larger than predicted one. 39.39% of mutations bring out one or both substituting aminoacid pairs which are absent in normal human menin. 59.60% of mutations lead to one or both substituting amino-acid pairs with their actual frequency smaller than predicted frequency. The results show that the mutation is highly likely to occur at the unpredictable amino-acid pairs, and the mutation has the trend to make an amino-acid pair approach predictable.

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“…RAD50 has also been shown to be underexpressed in breast cancer, although not as frequently as NBS1 or MRE11. 87 In mice, overexpression of RAD50 has been proven to have an antitumorigenic effect. 88 Loss of the MRN complex in cancer also has protumor effects due to failure to recruit the DNA damage sensor ATM, which is essential for recruitment of numerous DNA repair proteins.…”

Section: -86mentioning

confidence: 99%

DNA Repair Endonucleases: Physiological Roles and Potential as Drug Targets

Doherty

Madhusudan

2015

SLAS Discovery

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Genomic DNA is constantly exposed to endogenous and exogenous damaging agents. To overcome these damaging effects and maintain genomic stability, cells have robust coping mechanisms in place, including repair of the damaged DNA. There are a number of DNA repair pathways available to cells dependent on the type of damage induced. The removal of damaged DNA is essential to allow successful repair. Removal of DNA strands is achieved by nucleases. Exonucleases are those that progressively cut from DNA ends, and endonucleases make single incisions within strands of DNA. This review focuses on the group of endonucleases involved in DNA repair pathways, their mechanistic functions, roles in cancer development, and how targeting these enzymes is proving to be an exciting new strategy for personalized therapy in cancer.

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The importance of making ends meet: Mutations in genes and altered expression of proteins of the MRN complex and cancer

Cited by 46 publications

References 93 publications

Inactivation of the Nijmegen Breakage Syndrome Gene Leads to Excess Centrosome Duplication via the ATR/BRCA1 Pathway

Inactivation of the Nijmegen Breakage Syndrome Gene Leads to Excess Centrosome Duplication via the ATR/BRCA1 Pathway

Mutation Patterns in Human Menin

DNA Repair Endonucleases: Physiological Roles and Potential as Drug Targets

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