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- Lehmann, Laura C.,1991-Uppsala universitet,Molekylär systembiologi,Science for Life Laboratory, SciLifeLab,Deindl Lab (författare)
Allosteric control of ALC1-catalyzed nucleosome remodeling
- BokEngelska2021
Förlag, utgivningsår, omfång ...
- Uppsala :Acta Universitatis Upsaliensis,2021
- 45 s.
- electronicrdacarrier
Nummerbeteckningar
- LIBRIS-ID:oai:DiVA.org:uu-429899
- ISBN:9789151311289
- https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-429899URI
Kompletterande språkuppgifter
- Språk:engelska
- Sammanfattning på:engelska
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- SwePubSwePub
Klassifikation
Serie
- Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology,1651-6214 ;2009
Anmärkningar
- The defense will take place over Zoom:Join Zoom Meeting https://uu-se.zoom.us/j/9510129184Meeting ID: 951 012 9184Passcode: ALC1
- The genetic information of eukaryotic cells is packaged inside the nucleus as chromatin. This packaging restricts access to the DNA and therefore represents a barrier for processes such as DNA replication, repair, and gene expression. Specialized enzymes, termed ATP-dependent chromatin remodelers (remodelers), are involved in regulating the chromatin landscape by repositioning, ejecting, and altering the composition of nucleosomes, the smallest building blocks of chromatin. Remodelers are tightly regulated by post-translational modifications, nucleosomal features, as well as by their own domains and subunits. Dysregulation of remodeling activity has been implicated in severe disease states such as various types of cancer.ALC1/CHD1L (Amplified in Liver Cancer 1/Chromodomain-Helicase-DNA-binding protein 1-Like) is an oncogenic remodeler involved in DNA damage repair. This thesis investigates the molecular basis of ALC1 regulation, the role of the nucleosome and its features in ALC1 activation, as well as the role of this remodeler in DNA damage repair. The results presented in this thesis show that, without DNA damage, the catalytic domain of ALC1 adopts an inactive conformation that is stabilized through a conserved electrostatic interface with the macro domain of ALC1. Upon DNA damage, the binding of PAR chains to the macro domain displaces it from the ATPase motor of ALC1, thereby priming the remodeler for activation. Full activation additionally requires the interaction between a regulatory segment in the linker region of ALC1 and the nucleosome acidic patch. This interaction tethers the remodeler to the nucleosome and is required for coupling ATP hydrolysis to nucleosome remodeling. Additionally, investigations of ALC1 in vivo showed that the loss of ALC1 sensitizes cells to PARP inhibitors and is synthetic lethal with homologous recombination deficiency. This makes ALC1 a possible target for therapeutic drugs in combination with PARP inhibitors for cancers that are deficient in homologous recombination.
Ämnesord och genrebeteckningar
- NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
- NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
- NATURVETENSKAP Biologi Strukturbiologi hsv//swe
- NATURAL SCIENCES Biological Sciences Structural Biology hsv//eng
- ALC1
- CHD1L
- ATP-dependent chromatin remodeling
- nucleosome
- allosteric regulation
- autoinhibition
- macro domain
- PARP
- ADP-ribosylation
- DNA damage
- acidic patch
- Biology with specialization in Molecular Biology
- Biologi med inriktning mot molekylärbiologi
- Biology with specialization in Structural Biology
- Biologi med inriktning mot strukturbiologi
Biuppslag (personer, institutioner, konferenser, titlar ...)
- Deindl, Sebastian,Associate ProfessorUppsala universitet,Molekylär systembiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)sebde386 (preses)
- Knight, Stefan D.,ProfessorUppsala universitet,Strukturbiologi(Swepub:uu)stkni677 (preses)
- Müller-Planitz, Felix,ProfessorInstitute of Physiological Chemistry, Faculty of Medicine, TU Dresden (opponent)
- Uppsala universitetMolekylär systembiologi (creator_code:org_t)
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- Allosteric control of ALC1-catalyzed nucleosome remodeling (Sök publikationen i LIBRIS)
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