Regulation of Hyphal Morphogenesis and the DNA Damage Response by the Aspergillus nidulans ATM Homolog AtmA

Abstract

Ataxia telangiectasia (A-T) is an inherited disorder characterized by progressive loss of motor function and susceptibility to cancer. The most prominent clinical feature observed in A-T patients is the degeneration of Purkinje motor neurons. Numerous studies have emphasized the role of the affected gene product, ATM, in the regulation of the DNA damage response. However, in Purkinje cells, the bulk of ATM localizes to the cytoplasm and may play a role in vesicle trafficking. The nature of this function, and its involvement in the pathology underlying A-T, remain unknown. Here we characterize the homolog of ATM (AtmA) in the filamentous fungus Aspergillus nidulans. In addition to its expected role in the DNA damage response, we find that AtmA is also required for polarized hyphal growth. We demonstrate that an atmA mutant fails to generate a stable axis of hyphal polarity. Notably, cytoplasmic microtubules display aberrant cortical interactions at the hyphal tip. Our results suggest that AtmA regulates the function and/or localization of landmark proteins required for the formation of a polarity axis. We propose that a similar function may contribute to the establishment of neuronal polarity.

Genetic Interactions of the Aspergillus nidulans atmAATM Homolog With Different Components of the DNA Damage Response Pathway

“…As was previously seen (Malavazi et al 2006(Malavazi et al , 2007, and this work), the DatmA mutant strain showed decreased polar growth when compared to the wild-type strain (Table 4). The DchkA and DchkB mutant strains have not displayed polar growth defects while the double-mutant DchkA DchkB had decreased polar growth.…”

“…As previously shown by Malavazi et al (2006Malavazi et al ( , 2007, the DatmA mutant strain has an accelerated rate of proliferation, i.e., increased nuclear kinetics, when compared to the wild-type strain ( Figure 2B, first and second lanes). The double mutant showed an increased number of nuclei that was comparable to the DatmA mutant strain ( Figure 2B, third lane).…”

“…UvsB ATR displays an extensive web of genetic interactions with other proteins involved in the DNA damage response, including the Mre11 complex (ScaA NBS1 , MreA MRE11 , and SldI RAD50 ), the cdc2-related kinase NpkA, and SepB CTF4 (Fagundes et al 2004Gygax et al 2005;Malavazi et al 2005). Recently, we characterized the homolog of ATM (AtmA) in A. nidulans (Malavazi et al 2006(Malavazi et al , 2007. Here, we investigate genetic interactions of the A. nidulans atmA ATM homolog with different components of the DNA damage response pathway.…”

A Point Mutation in theAspergillus nidulans sonBNup98 Nuclear Pore Complex Gene Causes Conditional DNA Damage Sensitivity

“…This is because the sonB1 mutation is not synthetically lethal in combination with mutations in other cell cycle checkpoint regulators, including the A. nidulans orthologs of ATR, ATRIP, ATM, or the cdc2F mutant (Ye et al 1997;De Souza et al 1999;Hofmann and Harris 2000;Malavazi et al 2006). In addition, given that the sonB1 mutant was viable when combined with these cell cycle checkpoint mutants or the uvsC Rad51 .…”

“…To further investigate this, we determined if sonB1 mutants genetically interacted with mutants defective in different aspects of the DNA damage response in A. nidulans (Kafer and Mayor 1986;Yoon et al 1995;Kafer and May 1997;van Heemst et al 1997;Ye et al 1997;De Souza et al 1999;Hofmann and Harris 2000;Bruschi et al 2001;Semighini et al 2003;Malavazi et al 2006;Nayak et al 2006). Most striking were the genetic interactions between sonB1 and mutants of the A. nidulans NBS1 ortholog scaA NBS1 (Bruschi et al 2001).…”