Rapid DNA Synthesis during Early Drosophila Embryogenesis Is Sensitive to Maternal Humpty Dumpty Protein Function

By Lesly, Shera; Bandura, Jennifer L. et al. | Genetics, November 2017 | Go to article overview

Rapid DNA Synthesis during Early Drosophila Embryogenesis Is Sensitive to Maternal Humpty Dumpty Protein Function


Lesly, Shera, Bandura, Jennifer L., Calvi, Brian R., Genetics


GENOMIC DNA must be fully and accurately replicated when a cell divides. To achieve this, multiple steps of DNA replication are coordinated with different phases of the eukaryotic cell cycle. Prereplicative complexes (pre-RC) assemble onto replication origins in G1 phase, and are then activated by cell cycle kinases to initiate replication during S phase (Diffley et al. 1994; Parker et al. 2017; Tocilj et al. 2017; Yuan et al. 2017; Zhai et al. 2017). Upon initiation, a large replisome complex of proteins assembles at replication forks, which then migrate bidirectionally outward from the origin to synthesize new DNA strands (Pellegrini and Costa 2016). Reassembly of new pre-RCs is then inhibited until after the next mitosis, ensuring that each genomic region is duplicated only once per cell division (Hills and Diffley 2014). Problems with any of these steps of DNA replication can cause "replication stress" and DNA damage, which is sensed and corrected by cell cycle checkpoints (Hills and Diffley 2014). However, high levels of replication stress and checkpoint failure are major contributors to genome instability and cancer (Hills and Diffley 2014; Zeman and Cimprich 2014). In addition, hypomorphic mutations in a number of human genes that encode pre-RC and other replication proteins are the genetic cause of a class of developmental malformations known as microcephalic primordial dwarfisms (MPDs) (Klingseisen and Jackson 2011; Khetarpal et al. 2016). While much has been learned, it is still not fully understood how the DNA replication program is coordinated with development and perturbed in disease.

An extreme example of developmental modification to the DNA replication program occurs during early Drosophila embryogenesis. Embryogenesis begins with division of nuclei in a common syncytium, and the first nine of these "nuclear cleavage" divisions consist of only S and M phases (Rabinowitz 1941; Foe and Odell 1993; O'Farrell et al 2004). The duration of these first nine S/M cycles are rapid, ~8 min, during which genomic DNA is replicated in as little as 3 min by initiating replication from numerous, closely spaced origins (~10 kb apart) (Blumenthal et al. 1974; Sasaki et al. 1999). Because the majority of zygotic transcription does not begin until later during the mid-blastula transition (MBT), the early nuclear cleavage divisions are completely dependent on maternally encoded proteins (Edgar and O'Farrell 1989). Much remains unknown, however, about the regulation of the first nine S/M cycles, and how complete genome duplication exactly once per cycle is ensured. These early cycles lack a DNA replication or DNA damage checkpoint, although they do have a spindle assembly checkpoint (SAC) that monitors microtubulekinetochore attachments (Raff and Glover 1988; Girdham and Glover 1991; Fogarty etai. 1997; Sibon etai. 1997,1999,2000; Takada et al. 2003, 2007, 2015; Perez-Mongiovi et al. 2005; Crest et al. 2007; Oliveira et al. 2010). While the early, rapid S/M cycles may be an advantage by shortening developmental time, they also increase the risk of propagating DNA mutation into multiple cells that are descended from these early founder nuclei (O'Farrell et al. 2004).

Another extreme example of developmental modification to the DNA replication program occurs during Drosophila oogenesis when genes required for eggshell (chorion) synthesis are selectively amplified in DNA copy number (Spradling 1981). This developmental gene amplification occurs through DNA rereplication from amplicon origins at six loci in somatic follicle cells of the ovary (Claycomb and OrrWeaver 2005; Calvi 2006; Nordman and Orr-Weaver 2012). Similar to other origins, amplicon origins are bound by the pre-RC and activated by cell cycle kinases, and have been used as a model system to uncover conserved DNA replication mechanisms (Calvi et al. 1998; Asano and Wharton 1999; Royzman et al. 1999; Loebel et al. 2000; Aggarwal and Calvi 2004; Zhang and Tower 2004; Nordman et al. …

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Rapid DNA Synthesis during Early Drosophila Embryogenesis Is Sensitive to Maternal Humpty Dumpty Protein Function
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