The chromatin scaffold protein SAFB1 renders chromatin permissive for DNA damage signaling.
Although the general relevance of chromatin modifications for genotoxic stress signaling, cell-cycle checkpoint activation, and DNA repair is well established, how these modifications reach initial thresholds in order to trigger robust responses remains largely unexplored. Here, we identify the chromatin-associated scaffold attachment factor SAFB1 as a component of the DNA damage response and show that SAFB1 cooperates with histone acetylation to allow for efficient γH2AX spreading and genotoxic stress signaling. SAFB1 undergoes a highly dynamic exchange at damaged chromatin in a poly(ADP-ribose)-polymerase 1- and poly(ADP-ribose)-dependent manner and is required for unperturbed cell-cycle checkpoint activation and guarding cells against replicative stress. Altogether, our data reveal that transient recruitment of an architectural chromatin component is required in order to overcome physiological barriers by making chromatin permissive for DNA damage signaling, whereas the ensuing exclusion of SAFB1 may help prevent excessive signaling.
Chromosome Stability and Dynamics Group, Department of Disease Biology, the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
Matthias
M
Altmeyer
Luis
L
Toledo
Thorkell
T
Gudjonsson
Merete
M
Grøfte
Maj-Britt
MB
Rask
Claudia
C
Lukas
Vyacheslav
V
Akimov
Blagoy
B
Blagoev
Jiri
J
Bartek
Jiri
J
Lukas
D000107:Acetylation; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D036961:Matrix Attachment Region Binding Proteins / Q000235:genetics* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009152:Mutagenicity Tests; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034622:RNA Interference; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*
D002843:Chromatin; C468783:H2AX protein, human; D006657:Histones; D036961:Matrix Attachment Region Binding Proteins; D034521:Nuclear Matrix-Associated Proteins; D011960:Receptors, Estrogen; C109132:SAFB protein, human; D049452:Green Fluorescent Proteins; D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases