Life without ICE

HEADLINES

r=

, f?

Knowing when to quit NAVAS, T. A., ZHOU, Z. and ELLEDCE, 5. J. (1995) DNA polymerase E links the DNA replication machinery to the 5 phase checkpoint Cell 80, 29-39 The eukaryotic cell cycle consists of a series of coordinated and interdependent events; for example, chromosome segregation and cell division are linked to the completion

of DNA replication.

The linkage between

these events is in part

Distinct and essential functions of tropomyosins in yeast

imposed by checkpoint controls that arrest cell cycle progression in response to DNA damage or incomplete DNA replication. These stimuli also induce the

DREES, B., BROWN, C., BARRELL, B. G. and BRETSCHER, A. (1995)

expression of DNA repair genes. Many genes involved in this checkpoint signalling pathway have been identified

Tropomyosin is essential in yeast, yet the TPM7 and TPM2

in both mammalian cells and yeasts, but exactly how DNA damage or incomplete DNA replication is recognized and how the signal is conveyed to components of

products perform distinct

the transcription and cell cycle regulatory machinery remain a mystery. Proteins

functions I. Cell Biol. 128, 383-392

that form an integral part of DNA replication complexes seem logical candidates for the recognition

and signalling factors that alert the cell cycle machinery to

blockages or failures in DNA replication. However, most of the yeast DNA repli-

Tropomyosin

cation proteins are essential for cell viability and inactivation of them results in a checkpoint-mediated cell cycle arrest and induction of the DNA repair response.

identical a-helical coiled-coil chains that binds along the length of actin

Navas et al. provide evidence that DNA polymerase E of yeast contains two essential domains: an N-terminal polymerase domain, and a C-terminal domain

filaments

that may act as a sensor of replication blocks. Mutations in the DNA polymerase

isoforms of tropomyosins that differ in expression level, tissue distribution,

domain result in S phase arrest with an intact checkpoint

signalling pathway,

is a

dimer

of

two

in muscle and non-muscle

cells. Vertebrates

contain

while mutations in the C-terminal

domain result in failure to induce transcrip-

intracellular

tional responses to DNA damage

when DNA replication is hindered or when

binding properties, as well as in the proteins with which they interact.

DNA is damaged by treatment with mutagenic chemicals. Loss of the S phase checkpoint in the C-terminal mutants causes rapid cell death when DNA synthesis is inhibited, as the cells attempt chromosome segregation and mitosis without replicating their DNA. The checkpoint deficiency of these mutants can be suppressed by independently fragment

expressing a wild-type version of the C-terminal

of the polymerase, providing a strong demonstration

of the modular

localization

multiple

and F-actin-

The function of most vertebrate tropomyosin isoforms is not yet known. This report shows that tropomyosin diversity

also

exists

in

the

yeast

nature of this protein. Exactly how the polymerase signals to both the DNA damage repair systems and cell cycle machinery remains unknown, but now that the sensor has been found, characterization of other members of the

5. cerevisiae where TPM7 (described previously) and TPM2 (described for the first time in this report) encode

pathway may soon follow.

proteins

with

distinct

yet

overlap-

ping functions. TpmZp, which is present at about a sixth of the abundance of Tpmlp

in v&o, has 64.5%

sequence identity to Tpml p.

Life without ICE

Overexpression of TPM2 alters the pattern of bud emergence from the mother

LI, P. et al. (1995) Mice deficient in IL-1 B-converting enzyme are defective in production of mature IL-l B and resistant to endotoxic shock Cell 80,401-411 The proinflammatory

cytokine interleukin

1 p (IL-l B) is involved in the patho-

typical

cell from

situation

in

unipolar haploid

(the cells)

tothe bipolar pattern seen in diploids. This

phenotype

can

be

partially

suppressed by co-overexpression of TPMI. However, overexpression of TPM2 does not suppress the defec-

physiology of various diseases, such as rheumatoid arthritis, septic shock, inflammatory bowel disease and insulin-dependent diabetes mellitus. Active IL-l B is

tive organization

generated from its inactive precursor by the cysteine protease IL-1 B-converting

associated with a deletion

enzyme (ICE), which has been implicated in the induction of apoptosis. This paper reports that ICE-deficient mice appear to be developmentally and ana-

Finally, in contrast to loss of TPM7 or

of F-actin that

TPM2 alone, deletion and TPM2 is lethal.

is

of TPMI.

of both TPM7

tomically normal, with no demonstrable defect in apoptosis. They are unable to produce mature IL-l 8 but show no decrease in pro-IL-l B synthesis or release. In wildtype mice, injection of a high dose of lipopolysaccharide (LPS) caused the massive

These observations demonstrate that the two tropomyosins must

systemic release of proinflammatory cytokines such as TNF-cx, IL-18 and IL-1o(, and subsequent death from endotoxic shock within 30 h. In contrast, ICE-deficient mice were highly resistant to the lethal effects of LPS and 70% survived beyond seven

perform an essential function, yet are not functionally interchangeable. 5. cerevisiae offers a simple sys-

This month’s

days. High levels of IL-1 8 were present in the plasma of control mice at 30 h, but in

tem

Piero Morandini,

ICE-deficient mice IL-l 8 was undetectable at this time as was, unexpectedly, IL-l 0~. These results have implications for the role of ICE in apoptosis, the processing and/or release of IL-1 (Y, and the therapeutic potential of ICE inhibitors in endotoxic shock and other less acute inflammatory diseases such as rheumatoid arthritis.

tion of these different tropomyosins as well as to determine the gene products that interact with them.

TRENDS IN CELL BIOLOGY VOL. 5 MAY 1995

in which

to

study

the

func-

headlineswere contributed by David Stuart, SylvieTournier, Peter van der Sluijs and Dawn Walters.

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