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Biomolecules 2015, 5(4), 3396-3415; doi:10.3390/biom5043396

A Novel Aspect of Tumorigenesis—BMI1 Functions in Regulating DNA Damage Response

1,2,3
,
1,2,3
,
4
,
1,2,3
,
1,2,3
and
1,2,3,*
1
Department of Medicine, Division of Nephrology, McMaster University, Hamilton, ON L8S 4L8, Canada
2
Father Sean O’Sullivan Research Institute, Hamilton, ON L8N 4A6, Canada
3
The Hamilton Center for Kidney Research, St. Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada
4
The Genetics Laboratory, Longgang District Maternity and Child Healthcare Hospital, Longgang District, Shenzhen 518000, China
*
Author to whom correspondence should be addressed.
Academic Editors: Wolf-Dietrich Heyer, Thomas Helleday and Fumio Hanaoka
Received: 7 August 2015 / Revised: 23 October 2015 / Accepted: 26 November 2015 / Published: 1 December 2015
(This article belongs to the Special Issue DNA Damage Response)
View Full-Text   |   Download PDF [905 KB, uploaded 1 December 2015]   |  

Abstract

BMI1 plays critical roles in maintaining the self-renewal of hematopoietic, neural, intestinal stem cells, and cancer stem cells (CSCs) for a variety of cancer types. BMI1 promotes cell proliferative life span and epithelial to mesenchymal transition (EMT). Upregulation of BMI1 occurs in multiple cancer types and is associated with poor prognosis. Mechanistically, BMI1 is a subunit of the Polycomb repressive complex 1 (PRC1), and binds the catalytic RING2/RING1b subunit to form a functional E3 ubiquitin ligase. Through mono-ubiquitination of histone H2A at lysine 119 (H2A-K119Ub), BMI1 represses multiple gene loci; among these, the INK4A/ARF locus has been most thoroughly investigated. The locus encodes the p16INK4A and p14/p19ARF tumor suppressors that function in the pRb and p53 pathways, respectively. Its repression contributes to BMI1-derived tumorigenesis. BMI1 also possesses other oncogenic functions, specifically its regulative role in DNA damage response (DDR). In this process, BMI1 ubiquitinates histone H2A and γH2AX, thereby facilitating the repair of double-stranded DNA breaks (DSBs) through stimulating homologous recombination and non-homologous end joining. Additionally, BMI1 compromises DSB-induced checkpoint activation independent of its-associated E3 ubiquitin ligase activity. We review the emerging role of BMI1 in DDR regulation and discuss its impact on BMI1-derived tumorigenesis. View Full-Text
Keywords: BMI1; histone ubiquitination; DNA damage response (DDR); ATM; γH2AX; H2A; repair of double-stranded DNA breaks; checkpoint activation BMI1; histone ubiquitination; DNA damage response (DDR); ATM; γH2AX; H2A; repair of double-stranded DNA breaks; checkpoint activation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Lin, X.; Ojo, D.; Wei, F.; Wong, N.; Gu, Y.; Tang, D. A Novel Aspect of Tumorigenesis—BMI1 Functions in Regulating DNA Damage Response. Biomolecules 2015, 5, 3396-3415.

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