Collaboration of MLLT1/ENL, Polycomb and ATM for transcription and genome integrity.
Polycomb group (PcG) repress, whereas Trithorax group (TrxG) activate transcription for tissue development and cellular proliferation, and misregulation of these factors is often associated with cancer. ENL (MLLT1) and AF9 (MLLT3) are fusion partners of Mixed Lineage Leukemia (MLL), TrxG proteins, and are factors in Super Elongation Complex (SEC). SEC controls transcriptional elongation to release RNA polymerase II, paused around transcription start site. In MLL rearranged leukemia, several components of SEC have been found as MLL-fusion partners and the control of transcriptional elongation is misregulated leading to tumorigenesis in MLL-SEC fused Leukemia. It has been suggested that unexpected collaboration of ENL/AF9-MLL and PcG are involved in tumorigenesis in leukemia. Recently, we found that the collaboration of ENL/AF9 and PcG led to a novel mechanism of transcriptional switch from elongation to repression under ATM-signaling for genome integrity. Activated ATM phosphorylates ENL/AF9 in SEC, and the phosphorylated ENL/AF9 binds BMI1 and RING1B, a heterodimeric E3-ubiquitin-ligase complex in Polycomb Repressive complex 1 (PRC1), and recruits PRC1 at transcriptional elongation sites to rapidly repress transcription. The ENL/AF9 in SEC- and PcG-mediated transcriptional repression promotes DSB repair near transcription sites. The implication of this is that the collaboration of ENL/AF9 in SEC and PcG ensures a rapid response of transcriptional switching from elongation to repression to neighboring genotoxic stresses for DSB repair. Therefore, these results suggested that the collaboration of ENL/AF9 and PcG in transcriptional control is required to maintain genome integrity and may be link to the MLL-ENL/AF9 leukemia.
a Department of Translational Oncology , St. Marianna University , School of Medicine , Miyamae-Ku , Kawasaki , Japan.|b Division of Dynamic Proteome in Cancer and Aging , Institute of Development , Aging and Cancer , Tohoku University , Aoba-ku , Sendai , Japan.
Ayako
A
Ui
b Division of Dynamic Proteome in Cancer and Aging , Institute of Development , Aging and Cancer , Tohoku University , Aoba-ku , Sendai , Japan.
Akira
A
Yasui
D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D016678:Genome / Q000235:genetics*; D007938:Leukemia / Q000235:genetics / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D035602:Transcriptional Elongation Factors / Q000378:metabolism*
D063146:Polycomb-Group Proteins; D035602:Transcriptional Elongation Factors; D064007:Ataxia Telangiectasia Mutated Proteins
ATM; DSB repair; DSB-induced transcriptional repression; Polycomb; SEC