Disease relevance of MRE11A

• For ATM, MRE11A and XRCC4 we repeated the analysis in cases and controls separately to determine whether LD structure was consistent across breast cancer cases and controls [1].
• The cellular features resulting from these hMRE11 mutations are similar to those seen in A-T as well as NBS and include hypersensitivity to ionizing radiation, radioresistant DNA synthesis, and abrogation of ATM-dependent events, such as the activation of Jun kinase following exposure to gamma irradiation [2].
• Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder [3].
• Defective Mre11-dependent Activation of Chk2 by Ataxia Telangiectasia Mutated in Colorectal Carcinoma Cells in Response to Replication-dependent DNA Double Strand Breaks [4].
• Many viruses (herpes simplex virus type 1, polyomavirus, and human immunodeficiency virus type 1) require the activation of ataxia telangiectasia mutated protein (ATM) and/or Mre11 for a fully permissive infection [5].

Psychiatry related information on MRE11A

• Deficiency of the Mre11 DNA repair complex in Alzheimer's disease brains [6].

High impact information on MRE11A

• In contrast, concomitant interference with Nbs1-Mre11 and the Chk2-Cdc25A-Cdk2 pathways entirely abolishes inhibition of DNA synthesis induced by ionizing radiation, resulting in complete RDS analogous to that caused by defective ATM [7].
• The Mre11 complex is required for repair of hairpin-capped double-strand breaks and prevention of chromosome rearrangements [8].
• Our results suggest an additional role for the Mre11 complex in maintaining genome stability [8].
• The NBSp26 protein is not physically associated with the MRE11 complex, whereas the p70 species is physically associated with it [9].
• To clarify functions of the Mre11/Rad50 (MR) complex in DNA double-strand break repair, we report Pyrococcus furiosus Mre11 crystal structures, revealing a protein phosphatase-like, dimanganese binding domain capped by a unique domain controlling active site access [10].

Chemical compound and disease context of MRE11A

• The trypanosome mre11(-/-) strains were hypersensitive to phleomycin, a mutagen causing DNA double strand breaks (DSBs) but, in contrast to mre11(-/-) null mutants in other organisms and T. brucei rad51(-/-) null mutants, displayed no hypersensitivity to methyl methanesulfonate, which causes point mutations and DSBs [11].
• Using one-dimensional sodium dodecylsulfate polyacrylamide gel electrophoresis and Western blotting, we found that MRE11 is translocated from the nucleus to the cytoplasm when human U-1 melanoma or HeLa cells are heated for 15 min at 45.5 degrees C or when cells are heated after irradiation with 12 Gy of X rays [12].

Biological context of MRE11A

• RESULTS: Our results revealed that three of the five genes did not conform to a haplotype block structure (MRE11A, RAD50 and XRCC4) [1].
• Instead, we propose that the MRE11 complex functions at telomeres, possibly by modulating t-loop formation [13].
• In contrast to IR-induced ATM-S1981 phosphorylation, UV-induced ATM-S1981 phosphorylation does not require the Nbs1 C-terminus or Mre11 [14].
• In this article, we report the consequences of Mre11 dysfunction for the stability of mitotic and meiotic chromosomes in Arabidopsis thaliana [15].
• Mre11 deficiency in Arabidopsis is associated with chromosomal instability in somatic cells and Spo11-dependent genome fragmentation during meiosis [15].

Anatomical context of MRE11A

• The cellular consequences of this amino acid change, localized in the nuclease domain of the Mre11 protein, have been determined in fibroblast cultures established from two individuals [3].
• We present the isolation of hMRE11B cDNA from a human HeLa cell cDNA library as an MRE11 homolog [16].
• This mutation was selectively found in mismatch repair (MMR) defective cell lines and potentially identifies MRE11 as a novel target for MSI [17].
• In the mouse testis, Mre11 and Ku70 co-localized in nuclei of somatic cells and in the XY bivalent [18].
• We find that MRE11 associates specifically with rearranged Ig genes in hypermutating B cells, whereas APE1, the major AP-endonuclease in faithful base excision repair, does not [19].

Associations of MRE11A with chemical compounds

• HU and UV treatment also led to co-localization of hyperphosphorylated RPA and Mre11 to discrete detergent-resistant nuclear foci [20].
• By contrast, Mre11 TIFs were resistant to caffeine, consistent with previous findings on the Mre11 response to ionizing radiation [21].
• Furthermore, neocarzinostatin-induced Mre11 phosphorylation and nuclear focus formation are defective in AT and NBS cells, but not wild type cells [22].
• Our results showed that Mre11 went through cell cycle-dependent phosphorylation upon sodium arsenite treatment and this post-translational modification required NBS1 but not ATM [23].
• Herein we show that the MRE11 checkpoint protein is arginine methylated by PRMT1 [24].

Physical interactions of MRE11A

• The Mre11 complex is required for ATM activation and the G2/M checkpoint [25].
• Linkage between Werner syndrome protein and the Mre11 complex via Nbs1 [26].
• Consequently, the FHA/BRCT domain is likely to have a crucial role for both binding to histone and for relocalization of hMRE11/hRAD50 nuclease complex to the vicinity of DNA damage [27].
• Nbs1 is required for the Mre11 complex promotion of WRN helicase activity [26].
• Here, we discuss how WRN, the MRE11 complex and the ATR kinase could work together in response to replication blockage to avoid DNA replication fork collapse and genome instability [28].

Enzymatic interactions of MRE11A

• Protein kinase CK2 interacts with Chk2 and phosphorylates Mre11 on serine 649 [29].

Co-localisations of MRE11A

• In response to gamma-irradiation or mitomycin C, WRN leaves the nucleoli and co-localizes with the Mre11 complex in the nucleoplasm [26].

Regulatory relationships of MRE11A

• Downregulation of MDC1 expression by small interfering RNA yields a radio-resistant DNA synthesis (RDS) phenotype and prevents ionizing radiation-induced focus formation by the MRE11 complex [30].
• NBS cells are also deficient for radiation-induced nuclear foci containing Mre11, while those with Rad51 are unaffected [31].
• New data suggest that the Mre11 complex can directly activate the ATM checkpoint kinase at DNA breaks [32].
• Alternatively, the elevated yield of Mre11 foci positive cells following wortmannin treatment may reflect an overall perturbation to the signaling cascades regulated by wortmannin-sensitive PI3 related kinases [33].
• ATM and ATR promote Mre11 dependent restart of collapsed replication forks and prevent accumulation of DNA breaks [34].

Other interactions of MRE11A

• Indirect immunofluorescence demonstrated the presence of RAD50 and MRE11 at interphase telomeres [13].
• They showed high constitutive levels of Mre11 and Rad50 proteins compared with cells from normal individuals but a very low level of the Nbs1 protein [3].
• MRE11 mutations and impaired ATM-dependent responses in an Italian family with ataxia-telangiectasia-like disorder [35].
• We detect an increased association between WRN and the Mre11 complex after cellular exposure to gamma-irradiation [26].
• We also demonstrate that NBS1 binding can occur in the absence of interaction with hMRE11 or BRCA1 [27].

Analytical, diagnostic and therapeutic context of MRE11A

• Immunohistochemistry confirmed the impaired MRE11 expression and revealed NBS1-defective expression in MRE11 mutated cancers [17].
• Immunoblotting assays confirmed the absence of MRE11 expression in GCs with a 2 bp deletion [36].
• Microinjection of a His-tagged HdCdtB subunit, homologous to the mammalian DNase I, was sufficient to induce re-localization of the Mre11 complex 1 h post treatment [37].
• In vitro kinase assay with a series of truncated Mre11 proteins as substrates for CK2 and site-directed mutagenesis showed that serine 649 of Mre11 is mainly phosphorylated by CK2 in vitro [29].
• Therefore, the effect of 41.1 degrees C hyperthermia on the intracellular localization of the DNA double strand break repair protein, Mre11, was measured using in situ immunofluorescence and immunoblotting of soluble and insoluble cellular fractions [38].

References