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PMID: 7623808 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Identification of an origin of bidirectional DNA replication in the ubiquitously expressed mammalian CAD gene.

Molecular and cellular biology ·Vol. 15 ·No. 8 ·1995-08-00 ·Pages 4136-48

Kelly RE, DeRose ML, Draper BW, Wahl GM

Abstract

Most DNA replication origins in eukaryotes localize to nontranscribed regions, and there are no reports of origins within constitutively expressed genes. This observation has led to the proposal that there may be an incompatibility between origin function and location within a ubiquitously expressed gene. The biochemical and functional evidence presented here demonstrates that an origin of bidirectional replication (OBR) resides within the constitutively expressed housekeeping gene CAD, which encodes the first three reactions of de novo uridine biosynthesis (carbamoyl-phosphate synthetase, aspartate carbamoyltransferase, and dihydroorotase). The OBR was localized to a 5-kb region near the center of the Syrian hamster CAD transcriptional unit. DNA replication initiates within this region in the single-copy CAD gene in Syrian baby hamster kidney cells and in the large chromosomal amplicons that were generated after selection with N-phosphonacetyl-L-aspartate, a specific inhibitor of CAD. DNA synthesis also initiates within this OBR in autonomously replicating extrachromosomal amplicons (CAD episomes) located in an N-phosphonacetyl-L-aspartate-resistant clone (5P20) of CHOK1 cells. CAD episomes consist entirely of a multimer of Syrian hamster CAD cosmid sequences (cCAD1). These data limit the functional unit of replication initiation and timing control to the 42 kb of Syrian hamster sequences contained in cCAD1. In addition, the data indicate that the origin recognition machinery is conserved across species, since the same OBR region functions in both Syrian and Chinese hamster cells. Importantly, while cCAD1 exhibits characteristics of a complete replicon, we have not detected autonomous replication directly following transfection. Since the CAD episome was generated after excision of chromosomally integrated transfected cCAD1 sequences, we propose that prior localization within a chromosome may be necessary to "license" some biochemically defined OBRs to render them functional.

MeSH Terms
Animals Aspartate Carbamoyltransferase/genetics CHO Cells Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)/genetics Cosmids/genetics Cricetinae DNA DNA Replication Dihydroorotase/genetics Gene Amplification Mesocricetus Multienzyme Complexes/genetics Replication Origin/genetics Replicon/genetics
Chemicals
CAD trifunctional enzyme Multienzyme Complexes Okazaki fragments DNA Aspartate Carbamoyltransferase Dihydroorotase Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Kelly R E
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
DeRose M L
Draper B W
Wahl G M
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.15.8.4136
Published
1995-08-00
Pages
4136-48
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC230652
Subset
IM
Grants
NCI NIH HHS · CA521416 · United States
NIGMS NIH HHS · GM12957 · United States
NIGMS NIH HHS · GM521511 · United States
External Links
PubMed source DOI: 10.1128/MCB.15.8.4136 PMC Full Text View journal details
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