@article{725289410a27407d986539d9884a4c22,
title = "Mechanistic Insights into Regulation of the ALC1 Remodeler by the Nucleosome Acidic Patch",
abstract = "Upon DNA damage, the ALC1/CHD1L nucleosome remodeling enzyme (remodeler) is activated by binding to poly(ADP-ribose). How activated ALC1 recognizes the nucleosome, as well as how this recognition is coupled to remodeling, is unknown. Here, we show that remodeling by ALC1 requires a wild-type acidic patch on the entry side of the nucleosome. The cryo-electron microscopy structure of a nucleosome-ALC1 linker complex reveals a regulatory linker segment that binds to the acidic patch. Mutations within this interface alter the dynamics of ALC1 recruitment to DNA damage and impede the ATPase and remodeling activities of ALC1. Full activation requires acidic patch-linker segment interactions that tether the remodeler to the nucleosome and couple ATP hydrolysis to nucleosome mobilization. Upon DNA damage, such a requirement may be used to modulate ALC1 activity via changes in the nucleosome acidic patches.",
keywords = "acidic patch, ALC1, allosteric, CHD1L, chromatin, DNA damage, regulation, remodeler, remodeling, structure",
author = "Lehmann, {Laura C.} and Luka Bacic and Graeme Hewitt and Klaus Brackmann and Anton Sabantsev and Guillaume Gaullier and Sofia Pytharopoulou and Gianluca Degliesposti and Hanneke Okkenhaug and Song Tan and Alessandro Costa and Skehel, {J. Mark} and Boulton, {Simon J.} and Sebastian Deindl",
note = "Funding Information: We thank S.D. Knight for insightful comments; M. H{\"a}llberg, M. Carroni, and J. Conrad for assistance with cryo-EM data collection; J. Locke for early cryo-EM work; and A. Emmerich for preliminary smFRET experiments. This work was supported by the European Research Council ( StG, 714068 to S.D.; AdG, TelMetab to S.J.B.; and CoG, 820102 to A.C.), the KAW Foundation (grant KAW 019.0306 ), the Swedish Research Council (VR grant 2019-03534 ), and Cancerfonden (grant 19 0055 Pj ). Work at the Francis Crick Institute was funded by CRUK , Wellcome Trust , and MRC ( FC001065 to A.C. and FC0010048 to S.J.B.). S.J.B. acknowledges support from Wellcome Trust Senior Investigator and collaborative grants, and S.T. acknowledges support from NIH NIGMS grant R35 GM127034 . S.D. is an EMBO Young Investigator. Funding Information: We thank S.D. Knight for insightful comments; M. H?llberg, M. Carroni, and J. Conrad for assistance with cryo-EM data collection; J. Locke for early cryo-EM work; and A. Emmerich for preliminary smFRET experiments. This work was supported by the European Research Council (StG, 714068 to S.D.; AdG, TelMetab to S.J.B.; and CoG, 820102 to A.C.), the KAW Foundation (grant KAW 019.0306), the Swedish Research Council (VR grant 2019-03534), and Cancerfonden (grant 19 0055 Pj). Work at the Francis Crick Institute was funded by CRUK, Wellcome Trust, and MRC (FC001065 to A.C. and FC0010048 to S.J.B.). S.J.B. acknowledges support from Wellcome Trust Senior Investigator and collaborative grants, and S.T. acknowledges support from NIH NIGMS grant R35 GM127034. S.D. is an EMBO Young Investigator. S.D. conceived and oversaw the study. L.C.L. L.B. G.H. K.B. A.S. G.G. S.P. G.D. H.O. S.T. A.C. J.M.S. S.J.B. and S.D. designed and/or conducted experiments. A.S. collected/analyzed smFRET data. L.B. collected cryo-EM data, with help from G.G. G.G. analyzed cryo-EM data, with help from L.B. S.D. and S.J.B. wrote the manuscript, with input from all authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = dec,
day = "22",
doi = "10.1016/j.celrep.2020.108529",
language = "English",
volume = "33",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier BV",
number = "12",
}