title: A Novel Aspect of Tumorigenesis-BMI1 Functions in Regulating DNA Damage Response.
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.
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University, Hamilton, ON L8S 4L8, Canada. linx36@mcmaster.ca.|Father Sean O'Sullivan Research Institute, Hamilton, ON L8N 4A6, Canada. linx36@mcmaster.ca.|The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, ON L8N 4A6, Canada. linx36@mcmaster.ca.
authors.forename: Xiaozeng
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University, Hamilton, ON L8S 4L8, Canada. ojod@mcmaster.ca.|Father Sean O'Sullivan Research Institute, Hamilton, ON L8N 4A6, Canada. ojod@mcmaster.ca.|The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, ON L8N 4A6, Canada. ojod@mcmaster.ca.
authors.forename: Diane
authors.initials: D
authors.lastname: Ojo
authors.affiliation: The Genetics Laboratory, Longgang District Maternity and Child Healthcare Hospital, Longgang District, Shenzhen 518000, China. haowei727499@163.com.
authors.forename: Fengxiang
authors.initials: F
authors.lastname: Wei
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University, Hamilton, ON L8S 4L8, Canada. wongnyh@gmail.com.|Father Sean O'Sullivan Research Institute, Hamilton, ON L8N 4A6, Canada. wongnyh@gmail.com.|The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, ON L8N 4A6, Canada. wongnyh@gmail.com.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wong
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University, Hamilton, ON L8S 4L8, Canada. yangu@hotmail.ca.|Father Sean O'Sullivan Research Institute, Hamilton, ON L8N 4A6, Canada. yangu@hotmail.ca.|The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, ON L8N 4A6, Canada. yangu@hotmail.ca.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University, Hamilton, ON L8S 4L8, Canada. damut@mcmaster.ca.|Father Sean O'Sullivan Research Institute, Hamilton, ON L8N 4A6, Canada. damut@mcmaster.ca.|The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, ON L8N 4A6, Canada. damut@mcmaster.ca.
authors.forename: Damu
authors.initials: D
authors.lastname: Tang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*
chemical_list: C481581:MAPK7 protein, human; D048054:Mitogen-Activated Protein Kinase 7
keywords: ATM; BMI1; DNA damage response (DDR); H2A; checkpoint activation; histone ubiquitination; repair of double-stranded DNA breaks; γH2AX