similar to the activation of the E2 promoter via E2F, 
in each case involving a release of the responsible 
transcription factor from an inactive complex. 
Molecular Mechanisms of Polyadenylation 
The generation of the 3' terminus of the mature 
mRNA, commonly termed poly(A) site formation, is 
a critical event in the biogenesis of most mRNA mol- 
ecules. Moreover, since many transcription units 
encode multiple mRNAs that utilize alternative 
poly(A) sites, there is a potential regulatory role for 
polyadenylation. For instance, alternative poly (A) 
site choice is a contributing factor in the switch 
from production of the immunoglobulin heavy- 
chain mRNA that encodes the membrane-bound 
form of the protein to the mRNA encoding the se- 
creted form of the protein. Thus an understanding of 
the mechanisms of poly(A) site utilization, includ- 
ing the sequences directing the processing event as 
well as the factors involved in processing, is of con- 
siderable importance. 
One additional example of poly(A) site regula- 
tion is found during the course of an adenovirus in- 
fection. Five poly (A) sites are utilized within the 
major late transcription unit to produce more than 
20 distinct mRNAs during the late phase of infec- 
tion. The proximal half of the major late transcrip- 
tion unit is also expressed during the early phase of a 
viral infection. During this phase, the LI poly (A) 
site is used three times as frequently as the L3 
poly (A) site. In contrast, the L3 site is used three 
times more frequently than LI during the late phase 
of infection. Recent experiments have suggested 
that the recognition of the poly(A) site GU-rich 
downstream element by the CFl -processing factor 
may be a rate-determining step in poly(A) site 
selection. 
Work in Dr. Nevins's laboratory has demonstrated 
that the interaction of CFl with the LI poly (A) site 
is less stable than its interaction with the L3 poly(A) 
site. Moreover, there is a substantial decrease in the 
level of CFl activity when an adenovirus infection 
proceeds to the late phase, suggesting that this re- 
duction in the CFl activity, coupled with the rela- 
tive instability of the interaction with the LI 
poly (A) site, contributes to the reduced use of the 
LI poly (A) site in a late-infected cell. 
The project described above concerning molecu- 
lar mechanisms of polyadenylation was supported 
by a grant from the National Institutes of Health. 
Dr. Nevins is also Professor of Genetics at Duke 
University Medical Center. 
Articles 
Chellappan, S.P., Kraus, V.B., Kroger, B., Munger, 
K., Howley, P.M., Phelps, W.C., and Nevins, J.R. 
1992. Adenovirus El A, simian virus 40 tumor an- 
tigen, and human papillomavirus E7 protein share 
the capacity to disrupt the interaction between 
transcription factor E2F and the retinoblastoma 
gene product. Proc Natl Acad Sci USA 89:4549- 
4553. 
Devoto, S.H., Mudryj, M., Pines, J., Hunter, T., and 
Nevins, J.R. 1992. A cyclin A-protein kinase 
complex possesses sequence-specific DNA bind- 
ing activity: p33'^'"'^ is a component of the E2F- 
cyclin A complex. Ce// 68: 167-176. 
Hiebert, S.W., Chellappan, S.P., Horowitz, J.M., 
and Nevins, J.R. 1992. The interaction of RB 
with E2F coincides with an inhibition of the tran- 
scriptional activity of E2F. Genes Dev 6:177- 
185. 
Neill, S.D., and Nevins, J.R. 1991. Genetic analysis 
of the adenovirus E4 6/7 trans activator: interac- 
tion with E2F and induction of a stable DNA- 
protein complex are critical for activity. / Virol 
65:5364-5373. 
Nevins, J.R. 1991. Transcriptional activation by 
viral regulatory proteins. Trends Biochem Sci 
16:455-459. 
Nevins, J.R., Chellappan, S.P., Mudryj, M., Hie- 
bert, S., Devoto, S., Horowitz, J., Hunter, T., and 
Pines, J. 1991 ■ E2F transcription factor is a target 
for the Rb protein and the cyclin A protein. Cold 
Spring Harb Symp Quant Biol 56:157-162. 
Phelps, W.C., Bagchi, S., Barnes, J.A., Raychaudhuri, 
P., Kraus, V., Munger, K., Howley, P.M., and 
Nevins, J.R. 1991. Analysis of trans activation by 
human papillomavirus type 1 6 E7 and adenovirus 
12s ElA suggests a common mechanism. / Virol 
65:6922-6930. 
238 
