A La-related protein modulates 7SK snRNP integrity to suppress P-TEFb-dependent transcriptional elongation and tumorigenesis.
The general transcription factor P-TEFb stimulates RNA polymerase II elongation and cotranscriptional processing of pre-mRNA. Contributing to a functional equilibrium important for growth control, a reservoir of P-TEFb is maintained in an inactive snRNP where 7SK snRNA is a central scaffold. Here, we identify PIP7S as a La-related protein stably associated with and required for 7SK snRNP integrity. PIP7S binds and stabilizes nearly all the nuclear 7SK via 3' -UUU-OH, leading to the sequestration and inactivation of P-TEFb. This function requires its La domain and intact C terminus. The latter is frequently deleted in human tumors due to microsatellite instability-associated mutations. Consistent with the tumor suppressor role of a Drosophila homolog of PIP7S, loss of PIP7S function shifts the P-TEFb equilibrium toward the active state, disrupts epithelial differentiation, and causes P-TEFb-dependent malignant transformation. Through PIP7S modulation of P-TEFb, our data thus link a general elongation factor to growth control and tumorigenesis.
He
Nanhai
N
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Jahchan
Nadine S
NS
Hong
Eunmee
E
Li
Qiang
Q
Bayfield
Mark A
MA
Maraia
Richard J
RJ
Luo
Kunxin
K
Zhou
Qiang
Q
D020413:3' Untranslated Regions; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D014529:Uridine / Q000737:chemistry / Q000378:metabolism; D000097585:SS-B Antigen
D020413:3' Untranslated Regions; D001324:Autoantigens; D042925:Positive Transcriptional Elongation Factor B; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D017411:Ribonucleoproteins, Small Nuclear; D014157:Transcription Factors; D014529:Uridine; D000097585:SS-B Antigen; C476123:HEXIM1 protein, human