Journal
MOLECULAR CELL
Volume 68, Issue 5, Pages 847-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2017.10.017
Keywords
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Categories
Funding
- European Research Council (ERC)
- Swedish Research Council [VR 2015-04568]
- Knut and Alice Wallenberg Foundation [KAW/WAF 2014.0183]
- SciLifeLab
- ETH Zurich
- Cancer Research UK [FC0010048]
- UK Medical Research Council [FC0010048]
- Wellcome Trust [FC0010048]
- ERC
- Wellcome Trust
- VR computer time grant [SNIC2013-26-6]
- S.A. a FEBS Long-Term Fellowship
- Francis Crick Institute
- Swedish Research Council [2015-04568] Funding Source: Swedish Research Council
- Wellcome Trust [104558/Z/14/Z] Funding Source: Wellcome Trust
- Cancer Research UK [11581] Funding Source: researchfish
- Cancer Research UK
- The Francis Crick Institute [10048] Funding Source: researchfish
- Medical Research Council [MC_U105178788] Funding Source: researchfish
- The Francis Crick Institute [10267] Funding Source: researchfish
- Wellcome Trust [104558/Z/14/Z] Funding Source: researchfish
- MRC [MC_U105178788] Funding Source: UKRI
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Human ALC1 is an oncogene-encoded chromatin-remodeling enzyme required for DNA repair that possesses a poly(ADP-ribose) (PAR)-binding macro domain. Its engagement with PARylated PARP1 activates ALC1 at sites of DNA damage, but the underlying-mechanism remains unclear. Here, we establish a dual role for the macro domain in autoinhibition of ALC1 ATPase activity and coupling to nucleosome mobilization. In the absence of DNA damage, an inactive conformation of the ATPase is maintained by juxtaposition of the macro domain against predominantly the C-terminal ATPase lobe through conserved electrostatic interactions. Mutations within this interface displace the macro domain, constitutively activate the ALC1 ATPase independent of PARylated PARP1, and alter the dynamics of ALC1 recruitment at DNA damage sites. Upon DNA damage, binding of PARylated PARP1 by the macro domain induces a conformational change that relieves autoinhibitory interactions with the ATPase motor, which selectively activates ALC1 remodeling upon recruitment to sites of DNA damage.
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