Structure–function relationships of the Mre11 protein in the control of DNA end bridging and processing

Marsella, Antonio; Cassani, Corinne; Casari, Erika; Tisi, Renata; Longhese, Maria Pia

doi:10.1007/s00294-018-0861-5

Cited by 10 publications

(3 citation statements)

References 59 publications

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“…MRE11 can bind DNA after dimerization and is essential for DSB repair. 50 In Saccharomyces cerevisiae , the N‐terminal domain of MRE11 affects the excision activity of remote nucleases by mediating the association of MRX and Tel1/ATM with DNA DSBs, while the C‐terminal domain (CTD) promotes MRX‐tethering activity by interacting with RAD50 51 (Figure 2A ).…”

Section: The Mrn Complex In Hrmentioning

confidence: 99%

Double‐strand DNA break repair: molecular mechanisms and therapeutic targets

Tan,

Sun,

Zhao

et al. 2023

MedComm

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Double‐strand break (DSB), a significant DNA damage brought on by ionizing radiation, acts as an initiating signal in tumor radiotherapy, causing cancer cells death. The two primary pathways for DNA DSB repair in mammalian cells are nonhomologous end joining (NHEJ) and homologous recombination (HR), which cooperate and compete with one another to achieve effective repair. The DSB repair mechanism depends on numerous regulatory variables. DSB recognition and the recruitment of DNA repair components, for instance, depend on the MRE11–RAD50–NBS1 (MRN) complex and the Ku70/80 heterodimer/DNA–PKcs (DNA–PK) complex, whose control is crucial in determining the DSB repair pathway choice and efficiency of HR and NHEJ. In‐depth elucidation on the DSB repair pathway's molecular mechanisms has greatly facilitated for creation of repair proteins or pathways‐specific inhibitors to advance precise cancer therapy and boost the effectiveness of cancer radiotherapy. The architectures, roles, molecular processes, and inhibitors of significant target proteins in the DSB repair pathways are reviewed in this article. The strategy and application in cancer therapy are also discussed based on the advancement of inhibitors targeted DSB damage response and repair proteins.

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Section: The Mrn Complex In Hrmentioning

confidence: 99%

Double‐strand DNA break repair: molecular mechanisms and therapeutic targets

Tan,

Sun,

Zhao

et al. 2023

MedComm

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show abstract

“…Many components of these two DNA repair pathways have been identified. Although HR and NHEJ involve different sets of protein factors, Rad50, a component of the evolutionarily conserved MRX/MRN complex (Mre11-Rad50-Xrs2 in yeast or MRE11-Rad50-NBS1 in mammals), plays important roles in both pathways (Marsella et al, 2019). The MRX/MRN complex functions together with the Sae2 protein (CtIP in mammals) in initiation of DSB resection (Gobbini et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

FgRad50 Regulates Fungal Development, Pathogenicity, Cell Wall Integrity and the DNA Damage Response in Fusarium graminearum

et al. 2020

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Rad50 is a member of the double strand break repair epistasis group of proteins that play important roles in regulating DNA damage checkpoint signaling, telomere maintenance, homologous recombination and non-homologous end-joining in eukaryotes. However, the function of Rad50 in fungal plant pathogens remains unknown. In this study, we report the functional investigation of FgRad50 in the wheat head blight pathogen Fusarium graminearum. FgRad50 is an ortholog of Saccharomyces cerevisiae Rad50 that could restore the sensitivity of the yeast Rad50 mutant to DNA damage agents. The FgRad50 deletion mutant (FgRad50) exhibited defective vegetative growth, asexual/sexual development and virulence, as well as disrupted deoxynivalenol biosynthesis. Moreover, deletion of FgRad50 resulted in hypersensitivity to DNA damage agents. Unexpectedly, FgRad50 plays a key role in responses to cell wall-damaging agents by negatively regulating phosphorylation of FgMgv1, a MAP kinase in the cell wall integrity (CWI) pathway. Taken together, these results suggest that FgRad50 plays critical roles in fungal development, virulence and secondary metabolism in F. graminearum, as well as CWI and the DNA damage response.

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“…The MRN complex (MRE11, RAD50, NBS1) is a break sensor and adaptor in eukaryotes [5][6][7]. MRE11 and RAD50 are conserved from bacteria to humans [8] while NBS1 is only found in Eukaryota [9,10].…”

Section: Introductionmentioning

confidence: 99%

Mutation Spectra of the MRN (MRE11, RAD50, NBS1/NBN) Break Sensor in Cancer Cells

McPherson

Holub

Husbands

et al. 2020

Cancers

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The MRN complex (MRE11, RAD50, NBS1/NBN) is a DNA double strand break sensor in eukaryotes. The complex directly participates in, or coordinates, several activities at the break such as DNA resection, activation of the DNA damage checkpoint, chromatin remodeling and recruitment of the repair machinery. Mutations in components of the MRN complex have been described in cancer cells for several decades. Using the Catalogue of Somatic Mutations in Cancer (COSMIC) database, we characterized all the reported MRN mutations. This analysis revealed several hotspot frameshift mutations in all three genes that introduce premature stop codons and truncate large regions of the C-termini. We also found through evolutionary analyses that COSMIC mutations are enriched in conserved residues of NBS1/NBN and RAD50 but not in MRE11. Given that all three genes are important to carcinogenesis, we propose these differential enrichment patterns may reflect a more severe pleiotropic role for MRE11.

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Structure–function relationships of the Mre11 protein in the control of DNA end bridging and processing

Cited by 10 publications

References 59 publications

Double‐strand DNA break repair: molecular mechanisms and therapeutic targets

Double‐strand DNA break repair: molecular mechanisms and therapeutic targets

FgRad50 Regulates Fungal Development, Pathogenicity, Cell Wall Integrity and the DNA Damage Response in Fusarium graminearum

Mutation Spectra of the MRN (MRE11, RAD50, NBS1/NBN) Break Sensor in Cancer Cells

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