Loss of a DNA binding site within the tail of prelamin A contributes to altered heterochromatin anchorage by progerin.
Mutations in the lamin A/C (LMNA) gene that cause Hutchinson-Gilford progeria syndrome (HGPS) lead to expression of a protein called progerin with 50 amino acids deleted from the tail of prelamin A. In cells from patients with HGPS, both the amount and distribution of heterochromatin are altered. We designed in vitro assays to ask whether such alterations might reflect changes in chromatin, DNA and/or histone binding properties of progerin compared to wild-type lamin C-terminal tails. We show that progerin tail has a reduced DNA/chromatin binding capacity and modified trimethylated H3K27 binding pattern, offering a molecular mechanism for heterochromatin alterations related to HGPS.
Bruston
Francine
F
Unit of Functional and Adaptive Biology (BFA) affiliated with CNRS, Université Paris Diderot-Paris 7, Paris, France.
Delbarre
Erwan
E
Ostlund
Cecilia
C
Worman
Howard J
HJ
Buendia
Brigitte
B
Duband-Goulet
Isabelle
I
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006570:Heterochromatin / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A; D034882:Lamins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009687:Nuclear Proteins; D011371:Progeria / Q000235:genetics* / Q000378:metabolism*; D011498:Protein Precursors; D017384:Sequence Deletion
D002843:Chromatin; D006570:Heterochromatin; D034904:Lamin Type A; D034882:Lamins; D009687:Nuclear Proteins; D011498:Protein Precursors; C440308:lamin C; C090764:prelamin A; D004247:DNA