Study of the Regulation of Spindle Assembly Checkpoint Gene, Ubch 10 and Its Role in Genomic Instability in Human Cancer

Nath, Somsubhra (2011) Study of the Regulation of Spindle Assembly Checkpoint Gene, Ubch 10 and Its Role in Genomic Instability in Human Cancer. PhD thesis, Calcutta University.

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    Supervisors

    SupervisorsEmail
    Roychoudhury, Susanta

    Abstract

    Proper progression of mitosis depends on orderly ubiquitination and subsequent degradation of various mitotic inhibitors. This is monitored by spindle assembly checkpoint (SAC) that ensures accurate segregation of chromosomes during mitosis and thus prevents the onset of aneuploidy. UbcH10, an E2 ubiquitin-conjugating enzyme, plays a crucial role with mitotic E3 ubiquitin ligase anaphase promoting complex/ cyclosome (APC/C) in progression of and exit from mitosis. Similarly, SAC protein Cdc20 plays an important role in transition from metaphase to anaphase by activating APC/C. Cdc20 itself gets ubiquitinated by UbcH10 and thus activated to bind with APC/C. Any defect in chromosome alignment activates SAC by blocking Cdc20 and thus anaphase transition is arrested. On the other hand, defective execution of SAC is associated with aneuploidy and tumorigenesis. Indeed, both Cdc20 and UbcH10 are overexpressed in many cancer types and associated with defective SAC function leading to chromosomal instability. The precise mechanism of correlated overexpression of these two proteins remains elusive. In this study, we investigated the regulation of UbcH10 expression in Cdc20 overexpressed condition. We show that Cdc20 acts as a novel transcription factor regulating the expression of UBCH10. The WD40 domain of Cdc20 is required for this activity. This Cdc20 mediated transregulation involves acetylation dependent chromatin remodeling. Physical interaction between Cdc20 and APC/C-CBP/p300 complex and its subsequent recruitment to the UBCH10 promoter is involved in this transactivation process. Furthermore, this transcription regulatory function of Cdc20 was observed to be cell cycle specific. However, this Cdc20 transcription complex does not have any DNA binding domain (DBD). Toward that, we found a new role of DBD containing transcription factor E2F1 in regulation of UbcH10 expression. E2F1 interacts with and modulates the activity of Cdc20 transcription complex. Physical recruitment of Cdc20 transcription complex on UBCH10 promoter occurs through E2F1 consensus element. Moreover, Cdc20 transcription complex transactivates UBCH10 transcription in an E2F1 dependent manner.

    Item Type: Thesis (PhD)
    URI: http://www.eprints.iicb.res.in/id/eprint/1842
    Subjects: Molecular & Human Genetics
    Divisions: Indian Institute of Chemical Biology
    Depositing User: Mr Santanu Sadhukhan
    Date Deposited: 21 Mar 2013 12:43
    Last Modified: 21 Mar 2013 12:43
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