Disease relevance of mei-41

• We then compare five existing mei-41 alleles to the null with respect to known phenotypes (female sterility, cell cycle checkpoints, and MMS resistance) [1].
• Ataxia telangiectasia mutated (ATM) and ATR are essential for such cell-cycle control, but some observations suggest that they also play a direct role in DNA repair [2].
• Hypersensitivity of Drosophila mei-41 mutants to hydroxyurea is associated with reduced mitotic chromosome stability [3].
• The breakpoints of chromosomal aberrations identified within that walk establish that the entire mei-41 gene has been cloned [4].
• The high thermosensitive sterility, low fecundity, and premature aging of the male germ line were greatly exacerbated when males derived from either A or B crosses were deficient either in excision repair (mei-9 mutation) or in post-replication repair (mei-41 mutation) [5].

High impact information on mei-41

• Like ATM-deficient cells, mei-41 cells are exquisitely sensitive to ionizing radiation and display high levels of mitotic chromosome instability [6].
• The mei-41 gene of D. melanogaster is a structural and functional homolog of the human ataxia telangiectasia gene [6].
• We also demonstrate that mei-41 cells, like ATM-deficient cells, fail to show an irradiation-induced delay in the entry into mitosis that is characteristic of normal cells [6].
• We show that several Drosophila homologs of checkpoint genes, mei-41, grapes, and 14-3-3epsilon, regulate a DNA damage checkpoint in the developing eye [7].
• Similar to mei-41, mus304 is required for chromosome break repair and for genomic stability. mus304 animals also exhibit three developmental defects, abnormal bristle morphology, decreased meiotic recombination, and arrested embryonic development [7].

Chemical compound and disease context of mei-41

• Lethality is, however, potentially attributable to an abnormal enhancement of chromosomal aberrations by hydroxyurea in mutant mei-41 larvae [3].
• The observed lethality is not due to hypersensitivity of DNA synthesis in mei-41 larvae to hydroxyurea as assayed by tritiated thymidine incorporation [3].

Biological context of mei-41

• Of these, mutants deficient in DNA repair, mei-41 and okra, show progressive degeneration of imaginal discs and die as pupae, while other genotypes survive to adulthood after irradiation [8].
• mei-41 and bub1 block mitosis at two distinct steps in response to incomplete DNA replication in Drosophila embryos [9].
• BACKGROUND: During Drosophila oogenesis, unrepaired double-strand DNA breaks activate a mei-41-dependent meiotic checkpoint, which couples the progression through meiosis to specific developmental processes [10].
• These developmental phenotypes are unique to dATM, and both dATM and mei-41 have temporally distinct roles in G2 arrest after IR [11].
• We also tested the role of mei-41 in a recently characterized checkpoint that delays metaphase/anaphase transition after DNA damage in cellular embryos [1].

Anatomical context of mei-41

• X-Irradiation of spermatids significantly increased the preferential elimination of the P-element-bearing second chromosome in mei-41, DNA-repair-deficient dysgenic males, but had no effect in their DNA-repair-proficient brothers [12].

Associations of mei-41 with chemical compounds

• Grp/DChk1 is phosphorylated in a Mei-41/DATR-dependent manner in response to hydroxyurea and ionizing radiation, indicating that Mei-41/ATR is an upstream component in the Grp/DChk1 DNA replication and DNA-damage-response pathways [13].
• Here we report the generation of a null allele of mei-41, Drosophila ATM/ATR homolog, and the use of it to document a semidominant effect on a larval mitotic checkpoint and methyl methanesulfonate (MMS) sensitivity [1].
• The other protein complex (Factor 1) was not detectable in the post-replication repair-deficient mutant mus-104 [14].

Regulatory relationships of mei-41

• Accordingly, the CSN5 phenotype is suppressed by mutations in mei-41 or by mutations in mei-W68, which is required for double strand break formation [15].
• DNA-damaging agents and the mei-41 mutation enhanced the phenotype caused by RECQ5/QE overexpression [16].

Other interactions of mei-41

• The Mre11/Rad50/Nbs (MRN) complex and the two protein kinases ATM and ATR play critical roles in the response to DNA damage and telomere maintenance in mammalian systems [17].
• We propose a novel role for MEI-41 in DSB repair, independent of the Chk1/Chk2-mediated checkpoint response [2].
• Spontaneous mutation frequencies were higher in mei-9 and mei-41 males, and thus appropriate corrections were applied to the radiation data [18].
• In Drosophila, the maternally expressed mei-41 and grp genes are required for successful execution of the nuclear division cycles of early embryogenesis [19].
• ATM and ATR Pathways Signal Alternative Splicing of Drosophila TAF1 Pre-mRNA in Response to DNA Damage [20].

Analytical, diagnostic and therapeutic context of mei-41

• Molecular cloning of mei-41, a gene that influences both somatic and germline chromosome metabolism of Drosophila melanogaster [4].
• The frequencies of sex-linked recessive lethal mutations in flight groups were 2 and 3 times higher for wild type Canton-S and mei-41 strains, respectively, than those in ground control groups [21].
• Sequence analysis identified mutations, which, for most alleles, fall in the poorly characterized region outside the kinase domain; this allowed us to tentatively identify additional functional domains of MEI-41 that could be subjected to future structure-function studies of this key molecule [1].
• ATM/ATR kinases act as signal transducers in eukaryotic DNA damage and replication checkpoints [1].

References