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Published on: November 5, 2017
Phenotypic analysis of separation-of-function alleles of MEI-41, Drosophila ATM/ATR
Anne Laurençon1, Amanda Purdy, Jeff Sekelsky
1Molecular and Cellular Biology Department, University of California, Davis 95616, USA.
Abstract:
ATM/ATR kinases act as signal transducers in eukaryotic DNA damage and replication checkpoints. Mutations in ATM/ATR homologs have pleiotropic effects that range from sterility to increased killing by genotoxins in humans, mice, and Drosophila. 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. We also tested the role of mei-41 in a recently characterized checkpoint that delays metaphase/anaphase transition after DNA damage in cellular embryos. We then compare five existing mei-41 alleles to the null with respect to known phenotypes (female sterility, cell cycle checkpoints, and MMS resistance). We find that not all phenotypes are affected equally by each allele, i.e., the functions of MEI-41 in ensuring fertility, cell cycle regulation, and resistance to genotoxins are genetically separable. We propose that MEI-41 acts not in a single rigid signal transduction pathway, but in multiple molecular contexts to carry out its many functions. 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.
Insights
The Drosophila ATM/ATR homolog, mei-41, plays crucial roles in DNA damage response and cell cycle regulation. Different mei-41 alleles reveal that its functions in fertility, cell cycle control, and genotoxin resistance are genetically separable.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- ATM/ATR kinases are essential signal transducers for DNA damage and replication checkpoints in eukaryotes.
- Mutations in ATM/ATR homologs lead to diverse effects, including sterility and increased sensitivity to genotoxins across species.
Purpose of the Study:
- To generate and characterize a null allele of mei-41, the Drosophila homolog of ATM/ATR.
- To investigate the role of mei-41 in larval mitotic and DNA damage-induced metaphase/anaphase transition checkpoints.
- To compare existing mei-41 alleles with the null allele for phenotypes including female sterility, cell cycle checkpoints, and methyl methanesulfonate (MMS) resistance.
Main Methods:
- Generation of a null allele for the mei-41 gene in Drosophila.
- Phenotypic analysis of the null allele and five existing alleles.
- Assessment of larval mitotic checkpoint, DNA damage response checkpoints, female sterility, and MMS sensitivity.
Main Results:
- The null allele of mei-41 exhibits a semidominant effect on a larval mitotic checkpoint and MMS sensitivity.
- mei-41 plays a role in the DNA damage-induced checkpoint that delays metaphase/anaphase transition.
- Different mei-41 alleles differentially affect phenotypes, indicating genetic separability of MEI-41 functions.
Conclusions:
- The functions of MEI-41 in fertility, cell cycle regulation, and genotoxin resistance are genetically separable.
- MEI-41 likely functions in multiple molecular contexts rather than a single rigid pathway.
- Sequence analysis suggests potential novel functional domains in MEI-41 outside the kinase domain, warranting further structure-function studies.
