Structure and dynamics of the chromatin remodeler ALC1 bound to a PARylated nucleosome

Bacic, Luka (author): Uppsala universitet,Molekylär systembiologi,Science for Life Laboratory, SciLifeLab

Gaullier, Guillaume (author): Uppsala universitet,Molekylär systembiologi,Science for Life Laboratory, SciLifeLab

Sabantsev, Anton (author): Uppsala universitet,Molekylär systembiologi,Science for Life Laboratory, SciLifeLab

Lehmann, Laura C. (author): Uppsala universitet,Molekylär systembiologi,Science for Life Laboratory, SciLifeLab

Brackmann, Klaus (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Molekylär systembiologi

Dimakou, Despoina (author): Uppsala universitet,Molekylär systembiologi,Science for Life Laboratory, SciLifeLab

Halic, Mario (author): St Jude Childrens Res Hosp, Dept Struct Biol, 332 N Lauderdale St, Memphis, TN 38105 USA.

Deindl, Sebastian (author): Uppsala universitet,Molekylär systembiologi,Science for Life Laboratory, SciLifeLab

(creator_code:org_t)

Related links:: https://doi.org/10.7...; show more...; https://urn.kb.se/re...; https://doi.org/10.7...; show less...

Abstract Subject headings

The chromatin remodeler ALC1 is recruited to and activated by DNA damage-induced poly(ADP-ribose) (PAR) chains deposited by PARP1/PARP2/HPF1 upon detection of DNA lesions. ALC1 has emerged as a candidate drug target for cancer therapy as its loss confers synthetic lethality in homologous recombination-deficient cells. However, structure-based drug design and molecular analysis of ALC1 have been hindered by the requirement for PARylation and the highly heterogeneous nature of this post-translational modification. Here, we reconstituted an ALC1 and PARylated nucleosome complex modified in vitro using PARP2 and HPF1. This complex was amenable to cryo-EM structure determination without cross-linking, which enabled visualization of several intermediate states of ALC1 from the recognition of the PARylated nucleosome to the tight binding and activation of the remodeler. Functional biochemical assays with PARylated nucleosomes highlight the importance of nucleosomal epitopes for productive remodeling and suggest that ALC1 preferentially slides nucleosomes away from DNA breaks.

By the author/editor: Bacic, Luka; Gaullier, Guilla ...; Sabantsev, Anton; Lehmann, Laura C ...; Brackmann, Klaus; Dimakou, Despoin ...; show more...; Halic, Mario; Hewitt, Graeme; Boulton, Simon J ...; Deindl, Sebastia ...; show less...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

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