A genetic screen for dominant modifiers of a cyclin E hypomorphic mutation identifies novel regulators of S-phase entry in drosophila

Anthony Brumby, Julie Secombe, Julie Horsfield, Michelle Coombe, Nancy Amin, Deborah Coates, Robert Saint, Helena Richardson

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

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, DmcycEJP, 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 DmcycEJP rough eye phenotype. We have focused on the DmcycEJP 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(DmcycEJP) tested suppress the DmcycEJP 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. DmcycEJP 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 (αPS3-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.

Original languageEnglish (US)
Pages (from-to)227-251
Number of pages25
JournalGenetics
Volume168
Issue number1
DOIs
StatePublished - Sep 2004
Externally publishedYes

Fingerprint

Cyclin E
S Phase
Suppressor Genes
Drosophila
Mutation
Chromatin Assembly and Disassembly
Cell Adhesion
Genes
Phenotype
Larva
Alleles
Modifier Genes
Microtubule Proteins
Neoplasms
Cell Polarity
Phase Transition
X Chromosome
Integrins
Diptera
Carrier Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

A genetic screen for dominant modifiers of a cyclin E hypomorphic mutation identifies novel regulators of S-phase entry in drosophila. / Brumby, Anthony; Secombe, Julie; Horsfield, Julie; Coombe, Michelle; Amin, Nancy; Coates, Deborah; Saint, Robert; Richardson, Helena.

In: Genetics, Vol. 168, No. 1, 09.2004, p. 227-251.

Research output: Contribution to journalArticle

Brumby, Anthony ; Secombe, Julie ; Horsfield, Julie ; Coombe, Michelle ; Amin, Nancy ; Coates, Deborah ; Saint, Robert ; Richardson, Helena. / A genetic screen for dominant modifiers of a cyclin E hypomorphic mutation identifies novel regulators of S-phase entry in drosophila. In: Genetics. 2004 ; Vol. 168, No. 1. pp. 227-251.
@article{30cbda3f0734420ba1d530b1dda619e6,
title = "A genetic screen for dominant modifiers of a cyclin E hypomorphic mutation identifies novel regulators of S-phase entry in drosophila",
abstract = "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, DmcycEJP, 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 DmcycEJP rough eye phenotype. We have focused on the DmcycEJP 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(DmcycEJP) tested suppress the DmcycEJP 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. DmcycEJP 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 (αPS3-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.",
author = "Anthony Brumby and Julie Secombe and Julie Horsfield and Michelle Coombe and Nancy Amin and Deborah Coates and Robert Saint and Helena Richardson",
year = "2004",
month = "9",
doi = "10.1534/genetics.104.026617",
language = "English (US)",
volume = "168",
pages = "227--251",
journal = "Genetics",
issn = "0016-6731",
publisher = "Genetics Society of America",
number = "1",

}

TY - JOUR

T1 - A genetic screen for dominant modifiers of a cyclin E hypomorphic mutation identifies novel regulators of S-phase entry in drosophila

AU - Brumby, Anthony

AU - Secombe, Julie

AU - Horsfield, Julie

AU - Coombe, Michelle

AU - Amin, Nancy

AU - Coates, Deborah

AU - Saint, Robert

AU - Richardson, Helena

PY - 2004/9

Y1 - 2004/9

N2 - 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, DmcycEJP, 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 DmcycEJP rough eye phenotype. We have focused on the DmcycEJP 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(DmcycEJP) tested suppress the DmcycEJP 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. DmcycEJP 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 (αPS3-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.

AB - 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, DmcycEJP, 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 DmcycEJP rough eye phenotype. We have focused on the DmcycEJP 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(DmcycEJP) tested suppress the DmcycEJP 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. DmcycEJP 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 (αPS3-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.

UR - http://www.scopus.com/inward/record.url?scp=5144235403&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=5144235403&partnerID=8YFLogxK

U2 - 10.1534/genetics.104.026617

DO - 10.1534/genetics.104.026617

M3 - Article

C2 - 15454540

AN - SCOPUS:5144235403

VL - 168

SP - 227

EP - 251

JO - Genetics

JF - Genetics

SN - 0016-6731

IS - 1

ER -