The G2 DNA damage checkpoint: Could this ancient regulator be the Achilles heel of cancer?

Abstract

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 G1 is propagated through

activation of the tumor suppressor p53, which is mutated in many cancers. 

Chk1, a serine/threonine kinase, controls checkpoint responses in G2.  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, G2 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 G2 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.

Genetic studies regarding cell cycle progression in simple model organisms such

as the yeasts have been extremely informative for understanding these

processes in human cells – both in normal development, and in cancer. All

eukaryotes share many of the controls over cell cycle progression, particularly

those functioning at the transition from G2 into mitosis. However, human cells

have acquired additional controls not present in the yeasts that act in G1 to

coordinate extracellular signals with cell cycle progression, and to direct the

alternative cell fates of senescence and apoptosis. Such controls are frequently

mutated in tumor cells, and thus the resulting cancer cell cycle more closely

resembles the more primitive controls in the yeasts. In both systems, studies of

how cell cycle progression is influenced by genome integrity checkpoints has

revealed a complex and highly conserved signaling cascade also functioning at

the G2 to mitosis (G2/M) transition. This checkpoint may represent an “Achilles

heel” by which the differences between somatic and tumor cell cycles may be

exploited to selectively kill tumor cells.