UV-induced association of the CSB remodeling protein with chromatin requires ATP-dependent relief of N-terminal autorepression.
The ATP-dependent chromatin remodeler CSB is essential for transcription-coupled DNA repair, and mutations in CSB lead to Cockayne syndrome. Here, we examined the recruitment of CSB to chromatin after ultraviolet (UV) irradiation and uncovered a regulatory mechanism that ensures the specific association of this remodeler with chromatin. We demonstrate that ATP hydrolysis by CSB is essential for stable CSB-chromatin association after UV irradiation and that defects in this association underlie some forms of Cockayne syndrome. We also show that the N-terminal region of CSB negatively regulates chromatin association during normal cell growth. Of interest, in the absence of the negative regulatory region, ATP hydrolysis becomes dispensable for chromatin association, indicating that CSB uses energy from ATP hydrolysis to overcome the inhibitory effect imposed by its N-terminal region. Together, our results suggest that the recruitment of CSB to lesion-stalled transcription is an ATP-dependent process and involves a gross conformational change of CSB.
Lake
Robert J
RJ
Epigenetics and Progenitor Cells Keystone Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Geyko
Anastasia
A
Hemashettar
Girish
G
Zhao
Yu
Y
Fan
Hua-Ying
HY
D000251:Adenosine Triphosphatases / Q000502:physiology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000502:physiology / Q000528:radiation effects; D003057:Cockayne Syndrome / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008957:Models, Genetic; D000075223:Poly-ADP-Ribose Binding Proteins; D014466:Ultraviolet Rays
D002843:Chromatin; D000075223:Poly-ADP-Ribose Binding Proteins; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes