Deregulation of Rb-E2F1 axis causes chromosomal instability by engaging the transactivation function of Cdc20-APC/C complex.

Nath S, Chowdhury A, Dey S, Roychoudhury A, Ganguly A, Bhattacharyya D, Roychoudhury S

E2F family of transcription factors regulate genes involved in various aspects of cell cycle. Beyond the well-documented role in G1/S transition, mitotic regulation by E2F has also been reported. Proper mitotic progression is monitored by spindle assembly checkpoint (SAC). SAC ensures bipolar separation of chromosomes and thus, prevents aneuploidy. There are limited reports on the regulation of SAC by E2F. Our previous work identified the SAC protein Cdc20 as a novel transcriptional regulator of mitotic ubiquitin carrier protein UbcH10. However, none of the Cdc20 transcription complex proteins have any known DNA binding domain. Here, we show that E2F1-DP1 heterodimer is involved in recruitment of Cdc20 transcription complex to UBCH10 promoter and transactivation of the gene. We further show that inactivation of Rb can facilitate this transactivation process. Moreover, this E2F1-mediated regulation of UbcH10 influences mitotic progression. Deregulation of this pathway results in premature anaphase, chromosomal abnormalities and aneuploidy. We conclude that excess E2F1 due to Rb inactivation recruits Cdc20-APC/C transcription complex to deregulate the expression of UBCH10 leading to chromosomal instability in cancer cells.

Chromatin Shearing

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November, 2014



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