BMI1 is recruited to DNA breaks and contributes to DNA damage-induced H2A ubiquitination and repair

Vasudeva Ginjala; Karim Nacerddine; Atul Kulkarni; Jay Oza; Sarah J Hill; Ming Yao; Elisabetta Citterio; Maarten van Lohuizen; Shridar Ganesan

doi:10.1128/MCB.00981-10

BMI1 is recruited to DNA breaks and contributes to DNA damage-induced H2A ubiquitination and repair

Mol Cell Biol. 2011 May;31(10):1972-82. doi: 10.1128/MCB.00981-10. Epub 2011 Mar 7.

Authors

Vasudeva Ginjala¹, Karim Nacerddine, Atul Kulkarni, Jay Oza, Sarah J Hill, Ming Yao, Elisabetta Citterio, Maarten van Lohuizen, Shridar Ganesan

Affiliation

¹ Cancer Institute of New Jersey, Robert Wood Johnson Medical School-UMDNJ, New Brunswick, New Jersey, USA.

Abstract

DNA damage activates signaling pathways that lead to modification of local chromatin and recruitment of DNA repair proteins. Multiple DNA repair proteins having ubiquitin ligase activity are recruited to sites of DNA damage, where they ubiquitinate histones and other substrates. This DNA damage-induced histone ubiquitination is thought to play a critical role in mediating the DNA damage response. We now report that the polycomb protein BMI1 is rapidly recruited to sites of DNA damage, where it persists for more than 8 h. The sustained localization of BMI1 to damage sites is dependent on intact ATM and ATR and requires H2AX phosphorylation and recruitment of RNF8. BMI1 is required for DNA damage-induced ubiquitination of histone H2A at lysine 119. Loss of BMI1 leads to impaired repair of DNA double-strand breaks by homologous recombination and the accumulation of cells in G(2)/M. These data support a crucial role for BMI1 in the cellular response to DNA damage.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Ataxia Telangiectasia Mutated Proteins
Blotting, Western
Cell Cycle / genetics
Cell Cycle Proteins / metabolism
Chromatin Immunoprecipitation
DNA Breaks, Double-Stranded*
DNA Repair / genetics*
DNA-Binding Proteins / metabolism
Fluorescent Antibody Technique
HeLa Cells
Histones / metabolism*
Humans
Nuclear Proteins* / antagonists & inhibitors
Nuclear Proteins* / genetics
Nuclear Proteins* / metabolism
Phosphorylation
Polycomb Repressive Complex 1
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins* / antagonists & inhibitors
Proto-Oncogene Proteins* / genetics
Proto-Oncogene Proteins* / metabolism
RNA, Small Interfering
Repressor Proteins* / antagonists & inhibitors
Repressor Proteins* / genetics
Repressor Proteins* / metabolism
Signal Transduction / genetics
Tumor Suppressor Proteins / metabolism
Ubiquitin-Protein Ligases / metabolism
Ubiquitination

Substances

BMI1 protein, human
Cell Cycle Proteins
DNA-Binding Proteins
Histones
Nuclear Proteins
Proto-Oncogene Proteins
RNA, Small Interfering
RNF8 protein, human
Repressor Proteins
Tumor Suppressor Proteins
Polycomb Repressive Complex 1
Ubiquitin-Protein Ligases
ATM protein, human
ATR protein, human
Ataxia Telangiectasia Mutated Proteins
Protein Serine-Threonine Kinases