Cell cycle checkpoints are surveillance mechanisms that monitor and coordinate the order and ®delity of cell cycle events. When defects in the division program of a cell are detected, checkpoints prevent the pursuant cell cycle transition through regulation of the relevant cyclincdk complex(es). Checkpoints that respond to DNA damage have been described for the G1, S and G2 phases of the cell cycle. The p53 tumour suppressor is a key regulator of G1/S checkpoints, and can promote cell cycle delay or apoptosis in response to DNA damage. The importance of these events to cellular physiology is highlighted by the fact that tumours, in which p53 is frequently mutated, have widespread defects in the G1/S DNA damage checkpoints and a heightened level of genomic instability. G2/M DNA damage checkpoints have been de®ned by yeast genetics, though the genes in this response are conserved in mammals. We show here using biochemical and physiological assays that p53 is dispensable for a DNA damage checkpoint activated in the G2 phase of the cell cycle. Moreover, upregulation of p53 through serine 20 phosphorylation, does not occur in G2. Conversely, we show that the Chk1 protein kinase is essential for the human G2 DNA damage checkpoint. Importantly, inhibition of Chk1 in p53 de®cient cells greatly sensitizes them to radiation, validating the hypothesis of targeting Chk1 in rational drug design and development for anti-cancer therapies. Oncogene (2001) 20, 7453 ± 7463.

NIMA kinases appear to be the least functionally conserved mitotic regulators, being implicated in chromosome condensation in fungi and in spindle function in metazoans. We demonstrate here that the ®ssion yeast NIMA homologue, Fin1p, can induce profound chromosome condensation in the absence of the condensin and topoisomerase II, indicating that Fin1p-induced condensation differs from mitotic condensation. Fin1p expression is transcriptionally and posttranslationally cell cycle-regulated, with Fin1p kinase activity maximal from the metaphase±anaphase transition to G 1 . Fin1p is localized to the spindle pole body and ®n1D cells are hypersensitive to anti-microtubule drugs, synthetically lethal with a number of spindle mutants and require the spindle checkpoint for viability. Moreover, ®n1D cells show unusual and extensive elaborations of the nuclear envelope. These data support a role for Fin1p in spindle function and nuclear envelope transactions at or after the metaphase± anaphase transition that may be generally applicable to other NIMA-family members.