title: G1 checkpoint establishment in vivo during embryonic liver development.
abstract: BACKGROUND
  The DNA damage-mediated cell cycle checkpoint is an essential mechanism in the DNA damage response (DDR). During embryonic development, the characteristics of cell cycle and DNA damage checkpoint evolve from an extremely short G1 cell phase and lacking G1 checkpoint to lengthening G1 phase and the establishment of the G1 checkpoint. However, the regulatory mechanisms governing these transitions are not well understood. In this study, pregnant mice were exposed to ionizing radiation (IR) to induce DNA damage at different embryonic stages; the kinetics and mechanisms of the establishment of DNA damage-mediated G1 checkpoint in embryonic liver were investigated.
  
  
  RESULTS
  We found that the G2 cell cycle arrest was the first response to DNA damage in early developmental stages. Starting at E13.5/E15.5, IR mediated inhibition of the G1 to S phase transition became evident. Concomitantly, IR induced the robust expression of p21 and suppressed Cdk2/cyclin E activity, which might involve in the initiation of G1 checkpoint. The established G1 cell cycle checkpoint, in combination with an enhanced DNA repair capacity at E15.5, displayed biologically protective effects of repairing DNA double-strand breaks (DSBs) and reducing apoptosis in the short term as well as reducing chromosome deletion and breakage in the long term.
  
  
  CONCLUSIONS
  Our study is the first to demonstrate the establishment of the DNA damage-mediated G1 cell cycle checkpoint in liver cells during embryogenesis and its in vivo biological effects during embryonic liver development.
authors.affiliation: Department of Surgery, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, China. xqwang@hku.hk.
authors.forename: Xiao Qi
authors.initials: XQ
authors.lastname: Wang
authors.forename: Kwok Kin
authors.initials: KK
authors.lastname: Chan
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Ming
authors.forename: Vincent C H
authors.initials: VC
authors.lastname: Lui
authors.forename: Randy Y C
authors.initials: RY
authors.lastname: Poon
authors.forename: Chung Mau
authors.initials: CM
authors.lastname: Lo
authors.forename: Chris
authors.initials: C
authors.lastname: Norbury
authors.forename: Ronnie T P
authors.initials: RT
authors.lastname: Poon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D015153:Blotting, Western; D002869:Chromosome Aberrations / Q000528:radiation effects; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D015536:Down-Regulation / Q000528:radiation effects; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000528:radiation effects*; D008099:Liver / Q000196:embryology / Q000378:metabolism / Q000528:radiation effects*; D051379:Mice; D008813:Mice, Inbred ICR; D011247:Pregnancy; D011839:Radiation, Ionizing; D032681:Spectral Karyotyping; D013997:Time Factors; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; D051357:Cyclin-Dependent Kinase 2