The G(2) DNA damage checkpoint: could this ancient regulator be the Achilles heel of cancer?
The maintenance of genomic integrity is important in normal cell growth and organism development, as well as in the prevention of cancer. Cell cycle checkpoints allow the cell time to complete replication and repair DNA damage before it can pass to the next cell cycle stage. These checkpoints ensure faithful segregation of one undamaged copy of the genome to each daughter cell. In humans, a DNA damage-based checkpoint signal in G(1) is propagated through activation of the tumor suppressor p53, which is mutated in many cancers. Chk1, a serine/threonine kinase, controls checkpoint responses in G(2). Chk1 is activated by the concerted action of many upstream proteins and prevents a cell from entering mitosis with damaged or incompletely replicated DNA. This checkpoint is conserved from the fission yeast, Schizosaccharomyces pombe through to humans. However, unlike p53, G(2) checkpoint genes are rarely if ever mutated in cancer cells. This suggests that these genes are essential for tumor cell viability and may represent valid anti-cancer drug targets. This review will describe the current understanding of the G(2) checkpoint including how the human biology has been informed by studies in fission yeast. It will also discuss the present status and future of potential cancer therapies aimed at inactivating this signaling pathway in tumor cells.
Kuntz
Karen
K
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY, USA.
O'Connell
Matthew J
MJ
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D005075:Biological Evolution; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000071877:Checkpoint Kinase 1; D017124:Conserved Sequence; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000235:genetics / Q000378:metabolism; D016503:Drug Delivery Systems; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology*; D018816:Genes, cdc; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology; D051716:Replication Protein A / Q000502:physiology; D012568:Schizosaccharomyces / Q000166:cytology / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000502:physiology; D013045:Species Specificity; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004277:DNA, Single-Stranded; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D051716:Replication Protein A; D029702:Schizosaccharomyces pombe Proteins; C054852:7-hydroxystaurosporine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605873:Chk1 protein, S pombe; D019311:Staurosporine