- r Resolving telomere ends

CENCI, C. et al. (1997)

UbcDl, a Drosophila ubiquitin-conjugating enzyme required for proper telomere behavior

Genes Dev. 11, 863-875

Telomeres are important for the protection, replication and stabilization of chromosome ends and must be separated

during cell division to prevent chromosome breakage and chromosome nondisjunction during anaphase. This paper suggests that the ubiquitin-dependent proteolysis path- way is normally required to ensure proper telomere behav- iour during cell division.

The authors identified the UbcDI gene in a screen for mutations that affect the fidelity of chromosome segregation in Drosophila. Larvae bearing five independent mutant

alleles of UbcD7 showed frequent telomere-telomere inter- actions during mitosis and male meiosis that were not seen in wild-type cells. In some cases, the tips of sister chroma- tids were fused to the telomeres of the same chromosome, and, in other cases, they were fused to the telomeres of a different chromosome. In male meioses, these interactions were not resolved, resulting in frequent chromosome break- age during anaphase.

UbcD7 encodes a ubiquitin-conjugating enzyme that is

highly similar to UBC4 and UBCS of Saccharomyces cerevisiae. These results suggest that UBCDl activity is required for proper telomere behaviour during cell division in Drosophila, and the authors propose that the telomeric associations in mitosis and meiosis of UbcD7 mutants result from a failure to degrade one or more telomere-associated proteins that mediate telomere-telomere interactions. The identification of telomeric proteins that are targets of UBCDl will be

necessary to support this hypothesis, and recent studies suggest that telomere proteins can be ubiquitinated; Moazed and Johnson (Ce//86,667-677) identified Ubp3p, a deubiquitinating enzyme, as a binding partner of the telomere-binding protein Sir4p in 5. cerevisiae.

-

r

Getting rid of introns

HETZER, M., WURZER, C., SCHWEYEN, R. J. and MUELLER, M. W. (1997)

Trans-activation of group II intron splicing by nuclear US snRNA

Nature 386, 417-420

Most of us are probably aware that mature mRNA in eu- karyotes is made by the processing of pre-mRNA. It is the task of so-called spliceosomes (nuclear protein-RNA com- plexes) to remove the introns from pre-mRNA and splice the exons together to form the mature message. The spliceo- some numbers five RNA molecules (known as snRNAs) among its constituents, and one of these, lJ5 snRNA, plays a crucial catalytic role in the last step of splicing, that is holding the 5’ exon in position for its ligation to the 3’ exon. Not all intron-containing RNAs need the help of

a spliceosome though: group II introns can do the job by

trends in CELL BIOLOGY (Vol. 7) July 1997

themselves. In other words, they are catalytic RNAs, in which the intron-removing machinery is part of the intron itself. Their splicing mechanism is very similar to that of the

spliceosome, however, and in this paper Hetzer et al. demonstrate that a reqion within a qroup II intron acts as the functional counterpart of splice&omal US snRNA.

In yeast mitochondria, there is a self-splicing pre-mRNA, known as bll. This has a group II intron that possesses a subdomain (ID3) reminiscent of the stem-loop structure of U5 snRNA. When the ID3 sequence is deleted from bll, splicing is blocked prior to the exon-ligation stage, but normal splicing is restored when exogenous ID3 is added.

This shows that ID3 can act in trans, whereas it is normally cis acting, being part of the bll intron itself. Spliceosomal US snRNA, by contrast, normally works in trans, and, interest- ingly, exogenous US snRNA can rescue exon ligation of bll RNA lacking ID3. This suggests that US snRNA and the ID3 subdomain of bll have similar roles-that is, tethering of the free 5’ exon during splicing. These results argue that the catalytic core of group II introns and the spliceosome are alike,

and moreover they are consistent with the possibility that group II introns are the evolutionary predecessors of spliceo- somal snRNAs and, in particular, that the ID3 subdomain of group II introns gave rise to the precursor of U5 snRNA.

- fr Senescence:

solving an age-old problem?

SERRANO, M., LIN, A. W., McCURRACH, M. E., BEACH, D. and LOWE, S. W. (1997)

Oncogenic ras provokes premature cell senescence associated with accumulation of ~53 and pl 61NK40

Cell 88, 593-602

Tumour development not only requires increased cellular proliferation but also escape from safeguards, such as

apoptosis, that normally shut down inappropriate growth. In this paper, Serrano and colleagues identify a novel cel- lular defence mechanism against oncogene-induced hyper- proliferation. They show that retroviral transduction of an activated Ha-ras (H-rasV12) gene into primary human and

murine cells leads, after a short proliferative phase, to a GO/Cl arrest. By the available criteria, these arrested cells are indistinguishable from senescent cells: they exhibit a high cytoplasmic: nuclear ratio, have a 2n DNA content, lack serum-dependent upregulation of c-Fos and up- regulate both plasminogen activator inhibitor type 1 and senescence-associated P-galactosidase. This arrest is accom-

panied by upregulation of ~53, the p53-responsive gene product ~21, and ~16. Both p21 and ~16 are cyclin- dependent kinase (CDK) inhibitors and may mediate this arrest. This study raises several questions - for example, what triggers this senescent state? Is the senescent state reversible? More importantly, how do cells accumulate other mutations necessary for tumour formation if they senesce after a proliferative oncogenic event?

Interestingly, introduction of H-rasVl2 into murine cells

expressing the viral oncogene ElA or deficient for ~53 or ~16 function not only fails to arrest cells but is sufficient for transformation, indicating that functional ~53 and ~16 pathways are required for the arrest response. By contrast,

- Tills month’s

headhnes were

contributed by

Laura Attardl,

Jim Brugarolas,

Paul Femgno,

Peter Thomason,

Leslie Pond and

Flona Townsley.

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