Transcription linked to recombination: a gene-internal promoter coincides with the recombination hot spot II of the human MLL gene.
The MLL gene is frequently involved in chromosomal translocations associated with high-risk acute leukaemia. Infant and therapy-related acute leukaemia patients display chromosomal breakpoints preferentially clustered in the telomeric portion of the MLL breakpoint cluster region (SCII). Here, we demonstrate that SCII colocalizes with a gene-internal promoter element in the mouse and human MLL gene, respectively. The mRNA generated encodes an N-terminally truncated version of MLL that still exhibits many functional regions, including the C-terminal SET-domain. Etoposide-induced DNA double-strand breaks colocalize with the binding site of RNA polymerase II and the transcription initiation region, but not with a nearby Topo II consensus sequence. Thus, the observed genomic instability of the human MLL gene is presumably linked to transcriptional processes. The consequences of this novel finding for the creation of chromosomal translocations, the biology of the MLL protein and for MLL-mediated acute leukaemia are discussed.
Scharf
S
S
Institute of Pharmaceutical Biology/ZAFES, Biocenter, JWG-University of Frankfurt, Frankfurt/Main, Germany.
Zech
J
J
Bursen
A
A
Schraets
D
D
Oliver
P L
PL
Kliem
S
S
Pfitzner
E
E
Gillert
E
E
Dingermann
T
T
Marschalek
R
R
D000818:Animals; D002843:Chromatin; D005047:Etoposide; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II; D011995:Recombination, Genetic; D014158:Transcription, Genetic
D002843:Chromatin; C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D005047:Etoposide; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D012319:RNA Polymerase II