Drosophila Mus301/spindle-C Encodes a Helicase with an Essential Role in Double-Strand DNA Break Repair and Meiotic Progression

By McCaffrey, Ruth; St Johnston, Daniel et al. | Genetics, November 2006 | Go to article overview

Drosophila Mus301/spindle-C Encodes a Helicase with an Essential Role in Double-Strand DNA Break Repair and Meiotic Progression


McCaffrey, Ruth, St Johnston, Daniel, González-Reyes, Acaimo, Genetics


ABSTRACT

mus301 was identified independently in two genetic screens, one for mutants hypersensitive to chemical mutagens and another for maternal mutants with eggshell defects. mus301 is required for the proper specification of the oocyte and for progression through meiosis in the Drosophila ovary. We have cloned mus301 and show that it is a member of the Mus308 subfamily of ATP-dependent helicases and the closest homolog of human and mouse HEL308. Functional analyses demonstrate that Mus301 is involved in chromosome segregation in meiosis and in the repair of double-strand-DNA breaks in both meiotic and mitotic cells. Most of the oogenesis defects of mus301 mutants are suppressed by mutants in the checkpoint kinase Mei41 and in MeiW68, the Spo11 homolog that is thought to generate the dsDNA breaks that initiate recombination, indicating that these phenotypes are caused by activation of the DNA damage checkpoint in response to unrepaired Mei-W68-induced dsDNA breaks. However, neither mei-W68 nor mei41 rescue the defects in oocyte specification of mus301 mutants, suggesting that this helicase has another function in oocyte selection that is independent from its role in meiotic recombination.

(ProQuest Information and Learning: ... denotes formulae omitted.)

CELLS need to transmit an intact genome to ensure proper development, survival, and reproduction. The accurate replication of their genome requires both monitoring of DNA integrity and repairing of damages to DNA. Double-strand breaks (DSBs) in the DNA arise spontaneously during development or can be produced by ionizing radiations or by mechanical stress. The repair of DSBs is essential for genome stability and tumor suppression, as interactions between the ends of different DSBs can give rise to tumorigenic chromosome translocations (ELLIOT and JASIN 2002; ADAMS et al. 2003; SHIVJI and VENKITARAMAN 2004). In eukaryotes, checkpoints are in place to monitor the integrity of the DNA and to avoid the propagation of genomic defects. These checkpoints ensure that a subsequent step in the cell cycle is not initiated in the presence of damaged DNA, allowing additional time for the cell to correct the damage and stimulate the activity of highly conserved repair mechanisms. The DNA damage response in normal cells involves a series of signaling events that include sensors, transducers, and effectors. Central components of these checkpoints in mammals are the ATM/ATR family of phosphatidylinositol-3-OH-kinase-like serine/threonine kinases and their identified targets the checkpoint-1 (Chk1) and checkpoint-2 (Chk2) kinases (KURZ and LEES-MILLER 2004). Homologs of these exist in other eukaryotes where they play similar roles.

Recombination normally occurs during prophase I of meiosis and plays a critical role in homolog segregation and in the formation of viable gametes. Current models for meiotic recombination are based on the double-strand break repair model (SZOSTAK et al. 1983; BLANTON and SEKELSKY 2004). In budding yeast, recombination starts with the formation of double-strand DNA (dsDNA) breaks catalyzed by the type II DNA topoisomerase Spo11, the homolog of mei-W68 in Drosophila (CAO et al. 1990; MCKIM and HAYASHI-HAGIHARA 1998). Since the lack of function of mei-W68 abolishes meiotic crossing over and gene conversion, it is likely that recombination in the Drosophila ovary is also initiated by the occurrence of DSBs (MCKIM et al. 1998). In Drosophila, the repair of these dsDNA breaks is monitored by a meiotic checkpoint that involves the activity of the Mei-41 kinase (ATR homolog) (HARI et al. 1995) and of the Drosophila Chk2 homolog maternal nuclear kinase (mnk) (OISHI et al. 1998; ABDU et al. 2002). Its activation results in the modification of two effector proteins, Vasa andWee1. As a consequence, themeiotic cell cycle is regulated and the efficient translation of gurken (grk) mRNA is prevented (GHABRIAL and SCHÜPBACH 1999; ABDU et al. 2002). …

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Drosophila Mus301/spindle-C Encodes a Helicase with an Essential Role in Double-Strand DNA Break Repair and Meiotic Progression
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