The Drosophila Nbs Protein Functions in Multiple Pathways for the Maintenance of Genome Stability

Abstract

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. It has been previously shown that mutations in the Drosophila mre11 and rad50 genes cause both telomere fusion and chromosome breakage. Here, we have analyzed the role of the Drosophila nbs gene in telomere protection and the maintenance of chromosome integrity. Larval brain cells of nbs mutants display telomeric associations (TAs) but the frequency of these TAs is lower than in either mre11 or rad50 mutants. Consistently, Rad50 accumulates in the nuclei of wild-type cells but not in those of nbs cells, indicating that Nbs mediates transport of the Mre11/Rad50 complex in the nucleus. Moreover, epistasis analysis revealed that rad50 nbs, tefu (ATM) nbs, and mei-41 (ATR) nbs double mutants have significantly higher frequencies of TAs than either of the corresponding single mutants. This suggests that Nbs and the Mre11/Rad50 complex play partially independent roles in telomere protection and that Nbs functions in both ATR-and ATM-controlled telomere protection pathways. In contrast, analysis of chromosome breakage indicated that the three components of the MRN complex function in a single pathway for the repair of the DNA damage leading to chromosome aberrations.

Terminin: A protein complex that mediates epigenetic maintenance ofDrosophilatelomeres

“…These mutations also inhibit HOAP and HP1 localization at polytene chromosome ends. 36,37,[41][42][43] Consistent with these findings, mutations in mre11 prevent Moi localization at polytene chromosome telomeres. 31 Collectively, these results strongly suggest that terminin recruitment to telomeres requires the wild type function of the MRN complex.…”

“…31 Collectively, these results strongly suggest that terminin recruitment to telomeres requires the wild type function of the MRN complex. However, even in the absence of MRN activity, mitotic chromosomes retain the ability to recruit low levels of HOAP 36,37,[41][42][43] and, presumably, of the other terminin components. These low amounts of terminin are likely to provide a partial protection of telomeres, as suggested by the finding that rad50, mre11 and nbs mutants display much fewer TFs than cav mutants.…”

“…These low amounts of terminin are likely to provide a partial protection of telomeres, as suggested by the finding that rad50, mre11 and nbs mutants display much fewer TFs than cav mutants. 34,36,37,[41][42][43] Another DNA repair protein involved in Drosophila telomere protection is the ATM kinase. Null mutations in the tefu/atm gene result in lethality at late larval stages and cause both chromosome breakage and TFs in larval brain cells.…”

Drosophila telomeres: an exception providing new insights

“…Other proteins necessary for capping function are also major components of the DNA damage response (11), as has been found in mammals (34). In particular, members of the Mre11/Rad50/ Nbs (MRN) complex are required to maintain HOAP at the telomere and prevent telomere fusions (35)(36)(37)(38)(39), as are the ATM and ATR kinases (39)(40)(41)(42)(43). The ATM and ATR DNA damage response pathways are partially redundant.…”

TCTP directly regulates ATM activity to control genome stability and organ development in Drosophila melanogaster

“…Additionally, dATM participates in silencing the expression of genes adjacent to telomere ends (telomere position effect) 16,17 and in alternative splicing of pre-messenger RNA 18 . In Drosophila, although genetic evidence suggests that dATM is positively regulated by MRN 19 and negatively by histone deacetylase (RPD3) 10 , little is known how dATM is activated biochemically.…”