The role of the mammalian INO80 in maintaining genome stability

Alatwi, Hanan Eid A (2017) The role of the mammalian INO80 in maintaining genome stability. Doctoral thesis (PhD), University of Sussex.

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Linear DNA is packaged into higher-order structures termed chromatin, in which the majority of DNA sequences are structurally inaccessible and functionally inactive. Hence, chromatin must exist in a dynamic state to govern the accessibility of the DNA to various regulatory factors that control nuclear processes, such as transcription, DNA replication, and DNA repair. Accessibility in turn is mediated by post-translational modifications, histone variants, histone chaperones, and ATP-dependent chromatin remodelling complexes. In particular, these complexes, such as the multi-subunit INO80 complex, are characterized by their ability to utilise ATP hydrolysis to alter histone-DNA contact by the sliding, eviction, or exchange of histones or nucleosomes. Since its identification in 1999, many INO80 subunits have been purified and structurally characterized. Here, we structurally and biochemistry characterized the recently identified human INO80 YY1 subunit and demonstrated a role for YY1 together with RUVBL2, another INO80 subunit, in promoting DNA repair by homologous recombination (HR). Consequential to its chromatin-remodelling activity, INO80 plays multiple roles in cellular metabolism including DNA repair and chromosomal stability. Although evidence from yeast and mammals has indicated the involvement of INO80 in HR repair, the exact mechanism affected by INO80 therein remained unclear. Through a combination of live cell imaging and in vivo techniques, we revealed that in human cells the histone variant H2AZ is rapidly removed from damaged chromatin by INO80. Furthermore, we found that INO80 together with the histone chaperone, ANP32E, promotes HR by removing H2AZ from damaged chromatin. Finally, we verified that INO80 is required for the maintenance of chromosomal stability and that loss of INO80 in CIN+ tumour cells induced cell death. Therefore, INO80 may serve as a therapeutic target for the selective elimination of CIN+ tumour cells.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: Library Cataloguing
Date Deposited: 01 Jun 2017 15:12
Last Modified: 01 Jun 2017 15:12

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