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ISABEL ÁLVAREZ-TABARÉS Y COLS. ANAL. REAL ACAD. NAC. FARM.

to arrest in G2 phase after DNA damage. Instead they go into mitosis
and cells undergo a catastrophic mitosis. Consistent with a role for
Dis2 in release from G2 DNA damage checkpoint arrest, dis2? and
dis2.11 cells have a prolonged delay in response to DNA damage in
the G2 phase. However, Dis2 is unlikely to be the only protein
responsible for cell cycle re-entry following DNA damage checkpoints
arrest because the majority of dis2? cells do eventually recover, albeit
several hours after wild type cells. Moreover, the study by Elzen and
O’Connell also showed that Dis2, but not Sds21, was able to
dephosphorylate and inactivate Chk1 kinase in vitro and in vivo.
However, whether this dephosphorylation is responsible for the
release of the checkpoint arrest remains to be determined.

POSSIBLE FUNCTIONS OF DIS2 AT THE CENTROMERES

Multiple studies carried out in budding yeast and animals suggest
that PP1 may be counteracting Aurora kinase at the kinetochore. In
S. cerevisiae, temperature sensitive ipl1 mutants missegregate
chromosomes severely and die at elevated temperatures (47). The ts-
growth phenotype of such mutants can be partially suppressed by
mutations of S. cerevisiae PP1, GLC7+ (48). Furthermore, increasing
the dosage of GLC7 results in chromosome missegregation in wild-
type cells and lethality in ipl1 mutant cells, presumably due to
exacerbation of the ipl1 mutant phenotype. These observations
indicate that a reduction in Ipl1 protein kinase activity can be
compensated for by a reduction in PP1 activity, and exacerbated by
an increase in PP1 activity. This suggests that PP1 opposites Ipl1
protein kinase in regulating yeast chromosome segregation.

PP1 and Aurora may be counteracting each other in the control
of the phosphorylation state of kinetochore proteins. And the
phosphorylation state of kinetochore proteins may affect their
binding to centromeric DNA, their competence to bind microtubules
and/or their association with other kinetochore proteins.

In budding yeast, the phosphorylation state of Ndc10, a com-
ponent of the kinetochore complex CBF3, affects the microtubule-
binding activity of kinetochores reconstituted in cell extracts.
Interestingly, Ndc10 is hyperphosphorylated in glc7.10 mutant cell

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