dc.contributor.advisor | Alfieri C | |
dc.contributor.author | Wan, M | |
dc.contributor.editor | Alfieri, C | |
dc.date.accessioned | 2024-08-20T13:39:33Z | |
dc.date.available | 2024-08-20T13:39:33Z | |
dc.date.issued | 2024-08-20 | |
dc.identifier.citation | 2024 | en_US |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6365 | |
dc.description.abstract | In multicellular organisms, the vast majority of cells contain the same underlying DNA that is intricately packaged around histone proteins, forming organised chromatin structures. Epigenetic regulation enables gene expression control without altering the underlying DNA sequence and involves the molecular modification of DNA and histones to enable cells to adapt and fine-tune their gene expression programs to environmental cues and developmental signals. Modifications on histone tails, such as acetylation and methylation, results in the activation or repression of genes. Acetylation of lysine residues on histone tails activates transcription by weakening histone-DNA interactions. To reverse this process, acetyl groups can be removed by histone deacetylases (HDACs) which often exist in multi-subunit complexes, such as the mammalian SIN3B complex. Depletion of SIN3B inhibits the ability of proliferating cells to exit the cell cycle, leading to uncontrolled growth and division of cells, and thus, cancer. Furthermore, several lines of evidence suggest that the SIN3B complex is recruited to promoters of cell cycle genes by DREAM complex, a key regulator of cell cycle-dependent transcription. Given the significant roles that HDACs play, they are drug targets. However, structural information of holo-HDAC complexes, including the SIN3B complex, has been lacking.In this thesis, I aim to elucidate the mechanism of assembly, activation, and substrate selection of the human SIN3B complex. Furthermore, another aim is to understand how the SIN3B complex interacts with the DREAM complexes. Reported here are the first high-resolution structures of the full-length human SIN3B-HDAC complex by cryo-electron microscopy. We identify a novel mechanism of activation of class I HDACs and show that the PHD finger of the SIN3B histone recognition module recruits the histone tail and is responsible for substrate specificity. The SIN3B complex can deacetylate lysine residues on H3 tails from H3K14ac onwards, but not H3K9ac. Collectively, these findings may inform more specific and effective anti-cancer drugs and improve our understanding of the role of SIN3B in cell cycle regulation. | |
dc.language.iso | eng | en_US |
dc.publisher | Institute of Cancer Research (University Of London) | en_US |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | en_US |
dc.title | Structure and molecular function of the SIN3B HDAC complex in gene expression programs of cell cycle exit | en_US |
dc.type | Thesis or Dissertation | |
dcterms.accessRights | Public | |
dc.date.updated | 2024-08-20T13:36:05Z | |
rioxxterms.version | AO | en_US |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | en_US |
rioxxterms.licenseref.startdate | 2024-08-20 | |
rioxxterms.type | Thesis | en_US |
pubs.organisational-group | ICR | |
pubs.organisational-group | ICR/Primary Group | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Structural Biology | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Structural Biology/Molecular mechanisms of cell cycle regulation | |
pubs.organisational-group | ICR/Students | |
pubs.organisational-group | ICR/Students/PhD and MPhil | |
pubs.organisational-group | ICR/Students/PhD and MPhil/19/20 Starting Cohort | |
icr.researchteam | Mol mech cell cycle reg | en_US |
dc.contributor.icrauthor | Wan, Mandy | |
uketdterms.institution | Institute of Cancer Research | |
uketdterms.qualificationlevel | Doctoral | |
uketdterms.qualificationname | Ph.D | |
icr.provenance | Deposited by Mr Barry Jenkins (impersonating Dr Mandy Wan) on 2024-08-20. Deposit type is initial. No. of files: 1. Files: Mandy Wan PhD thesis.pdf | |
dc.type.qualificationlevel | Doctoral | |
dc.type.qualificationname | Ph.D | |