Ad. Yu et al., METAPHASE FRAGILITY OF THE HUMAN RNU1 AND RNU2 LOCI IS INDUCED BY ACTINOMYCIN-D THROUGH A P53-DEPENDENT PATHWAY, Human molecular genetics, 7(4), 1998, pp. 609-617
Infection of human cells with adenovirus 12 (Ad12), but not Ad2 or 5,
induces four specific sites of metaphase chromosome fragility: the U1
small nuclear RNA (snRNA) genes (the RNU1 locus), the U2 snRNA genes (
RNU2), the U1 snRNA pseudogenes (PSU1) and the 5S rRNA genes (RN5S). S
ignificantly, each of these sites corresponds to a multigene family en
coding a small, abundant structural RNA. We and others have shown prev
iously that Ad12-induced fragility of the RNU2 locus requires U2 snRNA
promoter elements, viral early functions and p53 function, but not vi
ral replication or integration, Rb function or chromosomal sequences f
lanking the RNU2 locus. Remarkably, we now find that very low doses of
actinomycin D (5-50 ng/ml) can phenocopy Ad12 infection: metaphase fr
agility of the RNU1 and RNU2 loci is induced specifically in the absen
ce of virus, and induction also requires U2 promoter elements and p53
function. Concurrently, it has been found by others that treatment wit
h cytosine arabinoside (araC), but not aphidicolin, can also phenocopy
Ad12 infection. We propose that Ad12 infection, actinomycin D and ara
C all induce a similar or identical global damage arrest signal (perha
ps a modification or altered conformation of p53) that preferentially
interferes with metaphase condensation of the RNU1 and RNU2 loci. The
RNU1 and RNU2 loci could be especially sensitive to this global signal
either because specialized U snRNA transcription factors interact uni
quely with the signal, or because the high concentration of short, act
ive transcription units hinders chromatin condensation.