The transposase domain protein Metnase/SETMAR suppresses chromosomal translocations.
Chromosomal translocations are common in leukemia, but little is known about their mechanism. Metnase (also termed SETMAR) is a fusion of a histone methylase and transposase protein that arose specifically in primates. Transposases were thought to be extinct in primates because they would mediate deleterious DNA movement. In primates, Metnase interacts with DNA Ligase IV (Lig IV) and promotes nonhomologous end-joining (NHEJ) DNA repair. We show here that the primate-specific protein Metnase can also enhance NHEJ in murine cells and can also interact with murine Lig IV, indicating that it integrated into the preexisting NHEJ pathway after its development in primates. Significantly, expressing Metnase in murine cells significantly reduces chromosomal translocations. We propose that the fusion of the histone methylase SET domain and the transposase domain in the anthropoid lineage to form primate Metnase promotes accurate intrachromosomal NHEJ and thereby suppresses interchromosomal translocations. Metnase may have been selected for because it has a function opposing transposases and may thus play a key role in suppressing translocations that underlie oncogenicity.
Wray
Justin
J
Division of Hematology-Oncology, Cancer Research and Treatment Center, Department of Medicine, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA.
Williamson
Elizabeth A
EA
Chester
Sean
S
Farrington
Jacqueline
J
Sterk
Rosa
R
Weinstock
David M
DM
Jasin
Maria
M
Lee
Suk-Hee
SH
Nickoloff
Jac A
JA
Hromas
Robert
R
D000818:Animals; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000502:physiology; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology*; D051379:Mice; D041681:NIH 3T3 Cells; D011993:Recombinant Fusion Proteins / Q000502:physiology*; D014178:Translocation, Genetic; D019895:Transposases / Q000502:physiology*
D004268:DNA-Binding Proteins; D011993:Recombinant Fusion Proteins; C111652:mariner transposases; D011495:Histone-Lysine N-Methyltransferase; D019895:Transposases; D011088:DNA Ligases; D000072481:DNA Ligase ATP