title: C. elegans MCM-4 is a general DNA replication and checkpoint component with an epidermis-specific requirement for growth and viability.
abstract: DNA replication and its connection to M phase restraint are studied extensively at the level of single cells but rarely in the context of a developing animal. C. elegans lin-6 mutants lack DNA synthesis in postembryonic somatic cell lineages, while entry into mitosis continues. These mutants grow slowly and either die during larval development or develop into sterile adults. We found that lin-6 corresponds to mcm-4 and encodes an evolutionarily conserved component of the MCM2-7 pre-RC and replicative helicase complex. The MCM-4 protein is expressed in all dividing cells during embryonic and postembryonic development and associates with chromatin in late anaphase. Induction of cell cycle entry and differentiation continues in developing mcm-4 larvae, even in cells that went through abortive division. In contrast to somatic cells in mcm-4 mutants, the gonad continues DNA replication and cell division until late larval development. Expression of MCM-4 in the epidermis (also known as hypodermis) is sufficient to rescue the growth retardation and lethality of mcm-4 mutants. While the somatic gonad and germline show substantial ability to cope with lack of zygotic mcm-4 function, mcm-4 is specifically required in the epidermis for growth and survival of the whole organism. Thus, C. elegans mcm-4 has conserved functions in DNA replication and replication checkpoint control but also shows unexpected tissue-specific requirements.
authors.affiliation: Developmental Biology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jerome
authors.initials: J
authors.lastname: Korzelius
authors.forename: Inge
authors.initials: I
authors.lastname: The
authors.forename: Suzan
authors.initials: S
authors.lastname: Ruijtenberg
authors.forename: Vincent
authors.initials: V
authors.lastname: Portegijs
authors.forename: Huihong
authors.initials: H
authors.lastname: Xu
authors.forename: H Robert
authors.initials: HR
authors.lastname: Horvitz
authors.forename: Sander
authors.initials: S
authors.lastname: van den Heuvel
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000502:physiology*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology*; D002454:Cell Differentiation; D002455:Cell Division; D002470:Cell Survival; D004261:DNA Replication; D004817:Epidermis / Q000502:physiology*; D016193:G1 Phase; D008938:Mitosis; D009928:Organ Specificity; D016196:S Phase
chemical_list: D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; C556688:MCM-4 protein, C elegans