Roles of human AND-1 in chromosome transactions in S phase

J Biol Chem. 2009 Jul 31;284(31):20718-28. doi: 10.1074/jbc.M806711200. Epub 2009 May 13.

Abstract

Coordinated execution of DNA replication, checkpoint activation, and postreplicative chromatid cohesion is intimately related to the replication fork machinery. Human AND-1/chromosome transmission fidelity 4 is localized adjacent to replication foci and is required for efficient DNA synthesis. In S phase, AND-1 is phosphorylated in response to replication arrest in a manner dependent on checkpoint kinase, ataxia telangiectasia-mutated, ataxia telangiectasia-mutated and Rad3-related protein, and Cdc7 kinase but not on Chk1. Depletion of AND-1 increases DNA damage, delays progression of S phase, leads to accumulation of late S and/or G2 phase cells, and induces cell death in cancer cells. It also elevated UV-radioresistant DNA synthesis and caused premature recovery of replication after hydroxyurea arrest, indicating that lack of AND-1 compromises checkpoint activation. This may be partly due to the decreased levels of Chk1 protein in AND-1-depleted cells. Furthermore, AND-1 interacts with cohesin proteins Smc1, Smc3, and Rad21/Scc1, consistent with proposed roles of yeast counterparts of AND-1 in sister chromatid cohesion. Depletion of AND-1 leads to significant inhibition of homologous recombination repair of an I-SceI-driven double strand break. Based on these data, we propose that AND-1 coordinates multiple cellular events in S phase and G2 phase, such as DNA replication, checkpoint activation, sister chromatid cohesion, and DNA damage repair, thus playing a pivotal role in maintenance of genome integrity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Death / radiation effects
  • Cell Line, Tumor
  • Cell Proliferation / radiation effects
  • Checkpoint Kinase 1
  • Chromatin / metabolism
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosomes, Human / metabolism*
  • Cohesins
  • DNA / biosynthesis
  • DNA Damage
  • DNA Repair / radiation effects
  • DNA-Binding Proteins / metabolism*
  • G2 Phase / radiation effects
  • Gene Knockdown Techniques
  • Humans
  • Phosphorylation / radiation effects
  • Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Radiation Tolerance / radiation effects
  • Recombination, Genetic / radiation effects
  • S Phase* / radiation effects
  • Tumor Suppressor Proteins / metabolism
  • Ultraviolet Rays

Substances

  • Cell Cycle Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • WDHD1 protein, human
  • DNA
  • Protein Kinases
  • CDC7 protein, human
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Protein Serine-Threonine Kinases