Genetics, Vol. 168, 227-251, September 2004, Copyright © 2004
doi:10.1534/genetics.104.026617

A Genetic Screen for Dominant Modifiers of a cyclin E Hypomorphic Mutation Identifies Novel Regulators of S-Phase Entry in Drosophila

Anthony Brumby^*,1, Julie Secombe^*,1,2, Julie Horsfield^,3, Michelle Coombe^*, Nancy Amin^*, Deborah Coates^*, Robert Saint^,4 and Helena Richardson^*,5

^* Peter MacCallum Cancer Centre, East Melbourne, Victoria, 3002, Australia
Department of Genetics/Centre for the Molecular Genetics of Development and Department of Molecular Biosciences, University of Adelaide, Adelaide, 5005, South Australia, Australia

⁵ Corresponding author: Peter MacCallum Cancer Centre, 7 St. Andrews Pl., East Melbourne, Victoria, 3002, Australia.
E-mail: helena.richardson{at}petermac.org

Cyclin E together with its kinase partner Cdk2 is a critical regulator of entry into S phase. To identify novel genes that regulate the G1- to S-phase transition within a whole animal we made use of a hypomorphic cyclin E mutation, DmcycE^JP, which results in a rough eye phenotype. We screened the X and third chromosome deficiencies, tested candidate genes, and carried out a genetic screen of 55,000 EMS or X-ray-mutagenized flies for second or third chromosome mutations that dominantly modified the DmcycE^JP rough eye phenotype. We have focused on the DmcycE^JP suppressors, S(DmcycE^JP), to identify novel negative regulators of S-phase entry. There are 18 suppressor gene groups with more than one allele and several genes that are represented by only a single allele. All S(DmcycE^JP) tested suppress the DmcycE^JP rough eye phenotype by increasing the number of S phases in the postmorphogenetic furrow S-phase band. By testing candidates we have identified several modifier genes from the mutagenic screen as well as from the deficiency screen. DmcycE^JP suppressor genes fall into the classes of: (1) chromatin remodeling or transcription factors; (2) signaling pathways; and (3) cytoskeletal, (4) cell adhesion, and (5) cytoarchitectural tumor suppressors. The cytoarchitectural tumor suppressors include scribble, lethal-2-giant-larvae (lgl), and discs-large (dlg), loss of function of which leads to neoplastic tumors and disruption of apical-basal cell polarity. We further explored the genetic interactions of scribble with S(DmcycE^JP) genes and show that hypomorphic scribble mutants exhibit genetic interactions with lgl, scab (PS3-integrin—cell adhesion), phyllopod (signaling), dEB1 (microtubule-binding protein—cytoskeletal), and moira (chromatin remodeling). These interactions of the cytoarchitectural suppressor gene, scribble, with cell adhesion, signaling, cytoskeletal, and chromatin remodeling genes, suggest that these genes may act in a common pathway to negatively regulate cyclin E or S-phase entry.

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