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Molecular mechanism...
Molecular mechanisms underlying the activation of ALC1 nucleosome remodeling
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- Bacic, Luka (author)
- Uppsala universitet,Molekylär systembiologi,Uppsala University,Deindl
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- Deindl, Sebastian (thesis advisor)
- Uppsala universitet,Molekylär systembiologi,Science for Life Laboratory, SciLifeLab
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- Knight, Stefan D. (thesis advisor)
- Uppsala universitet,Strukturbiologi
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- Lehtiö, Lari, Professor (opponent)
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland
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(creator_code:org_t)
- ISBN 9789151316451
- Uppsala : Acta Universitatis Upsaliensis, 2022
- English 46 s.
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Series: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, 1651-6214 ; 2213
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Abstract
Subject headings
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- Packaging DNA into chromatin represses essential DNA-based processes, such as transcription, DNA replication, and repair. To change the accessibility of DNA, cells have evolved a set of enzymes referred to as chromatin remodelers that act on the basic repeat unit of chromatin, the nucleosome. Chromatin remodelers are critical for normal cell physiology and development. Dysfunction or aberrant regulation of chromatin remodelers can lead to multisystem developmental disorders and cancers. DNA damage represents a major threat to eukaryotic cells. When DNA damage persists, the cell can enter programmed cell death. To avoid such a dramatic outcome, cells must rapidly recognize the DNA damage and trigger DNA repair pathways. An early event following DNA damage is the relaxation of chromatin. Chromatin relaxation depends on ATP consumption and ADP-ribosylation, where the site of DNA damage is marked with ADP-ribose units. ADP-ribose, in turn, can be recognized by the macro domain of the remodeler ALC1 (Amplified in Liver Cancer 1). ALC1 has therefore been implicated in the DNA damage response. In the absence of DNA damage, the macro domain of ALC1 is placed against its ATPase motor to inhibit its activity. However, it is unclear how ALC1, in its active state, engages the nucleosome. Moreover, the mechanism by which ALC1 is fully activated upon recruitment is poorly understood, and the impact of ALC1-catalyzed nucleosome sliding in the vicinity of a DNA damage site is unknown. This thesis investigates how ALC1 engages its substrate, the nucleosome, and how histone modifications can regulate ALC1 activity. Structural and biophysical approaches revealed an ALC1 regulatory segment that binds to the acidic patch, a prominent feature on the nucleosome surface. Further analysis showed that the interaction between ALC1 and the acidic patch is required to fully activate ALC1. Moreover, in vitro ADP-ribosylation of nucleosomes enabled us to form a stable complex of nucleosome-bound ALC1 amenable to structural determination by cryogenic electron microscopy. Our structural models visualize nucleosomal epitopes that play an important role in stimulating productive remodeling by ALC1, as confirmed by various biochemical approaches. Taken together, our data suggested a possible mechanism by which ALC1 could render DNA breaks more accessible to downstream repair factors. Since recent studies defined ALC1 as an attractive anti-cancer target, this thesis provides insights into the molecular mechanisms that regulate ALC1 activity as a potential starting point for structure-based drug development.
Subject headings
- NATURVETENSKAP -- Biologi -- Strukturbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Structural Biology (hsv//eng)
Keyword
- ALC1
- CHD1L
- nucleosome
- ADP-ribosylation
- chromatin
- remodeling
- PARP1
- HPF1
- DNA damage
- Biology with specialization in Structural Biology
- Biologi med inriktning mot strukturbiologi
- Biology with specialization in Structural Biology
- Biologi med inriktning mot strukturbiologi
- Biology with specialization in Structural Biology
- Biologi med inriktning mot strukturbiologi
Publication and Content Type
- vet (subject category)
- dok (subject category)
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