title: The super elongation complex family of RNA polymerase II elongation factors: gene target specificity and transcriptional output.
abstract: The elongation stage of transcription is highly regulated in metazoans. We previously purified the AFF1- and AFF4-containing super elongation complex (SEC) as a major regulator of development and cancer pathogenesis. Here, we report the biochemical isolation of SEC-like 2 (SEC-L2) and SEC-like 3 (SEC-L3) containing AFF2 and AFF3 in association with P-TEFb, ENL/MLLT1, and AF9/MLLT3. The SEC family members demonstrate high levels of polymerase II (Pol II) C-terminal domain kinase activity; however, only SEC is required for the proper induction of the HSP70 gene upon stress. Genome-wide mRNA-Seq analyses demonstrated that SEC-L2 and SEC-L3 control the expression of different subsets of genes, while AFF4/SEC plays a more dominant role in rapid transcriptional induction in cells. MYC is one of the direct targets of AFF4/SEC, and SEC recruitment to the MYC gene regulates its expression in different cancer cells, including those in acute myeloid or lymphoid leukemia. These findings suggest that AFF4/SEC could be a potential therapeutic target for the treatment of leukemia or other cancers associated with MYC overexpression.
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri, USA.
authors.forename: Zhuojuan
authors.initials: Z
authors.lastname: Luo
authors.forename: Chengqi
authors.initials: C
authors.lastname: Lin
authors.forename: Erin
authors.initials: E
authors.lastname: Guest
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Garrett
authors.forename: Nima
authors.initials: N
authors.lastname: Mohaghegh
authors.forename: Selene
authors.initials: S
authors.lastname: Swanson
authors.forename: Stacy
authors.initials: S
authors.lastname: Marshall
authors.forename: Laurence
authors.initials: L
authors.lastname: Florens
authors.forename: Michael P
authors.initials: MP
authors.lastname: Washburn
authors.forename: Ali
authors.initials: A
authors.lastname: Shilatifard
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D016259:Genes, myc; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D035602:Transcriptional Elongation Factors / Q000378:metabolism*
chemical_list: C099930:AFF2 protein, human; C097738:AFF3 protein, human; C471348:AFF4 protein, human; D018840:HSP70 Heat-Shock Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D012097:Repressor Proteins; D035602:Transcriptional Elongation Factors; D042925:Positive Transcriptional Elongation Factor B; D012319:RNA Polymerase II