Selective entrapment of extrachromosomally amplified DNA by nuclear budding and micronucleation during S phase

J Cell Biol. 1998 Mar 23;140(6):1307-20. doi: 10.1083/jcb.140.6.1307.

Abstract

Acentric, autonomously replicating extrachromosomal structures called double-minute chromosomes (DMs) frequently mediate oncogene amplification in human tumors. We show that DMs can be removed from the nucleus by a novel micronucleation mechanism that is initiated by budding of the nuclear membrane during S phase. DMs containing c-myc oncogenes in a colon cancer cell line localized to and replicated at the nuclear periphery. Replication inhibitors increased micronucleation; cell synchronization and bromodeoxyuridine-pulse labeling demonstrated de novo formation of buds and micronuclei during S phase. The frequencies of S-phase nuclear budding and micronucleation were increased dramatically in normal human cells by inactivating p53, suggesting that an S-phase function of p53 minimizes the probability of producing the broken chromosome fragments that induce budding and micronucleation. These data have implications for understanding the behavior of acentric DNA in interphase nuclei and for developing chemotherapeutic strategies based on this new mechanism for DM elimination.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antimetabolites
  • Bromodeoxyuridine
  • Cell Nucleus / genetics*
  • Cell Nucleus / pathology
  • DNA, Neoplasm / metabolism*
  • Extrachromosomal Inheritance / physiology*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Neuroendocrine Tumors
  • Replicon / physiology
  • S Phase / genetics*
  • Tumor Cells, Cultured / cytology
  • Tumor Cells, Cultured / physiology
  • Tumor Suppressor Protein p53 / physiology

Substances

  • Antimetabolites
  • DNA, Neoplasm
  • Tumor Suppressor Protein p53
  • Bromodeoxyuridine