Recruitment of lysine demethylase 2A to DNA double strand breaks and its interaction with 53BP1 ensures genome stability

Murilo T.D. Bueno; Marta Baldascini; Stéphane Richard; Noel F. Lowndes

doi:10.18632/oncotarget.24636

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Research Papers:

Recruitment of lysine demethylase 2A to DNA double strand breaks and its interaction with 53BP1 ensures genome stability

Murilo T.D. Bueno, Marta Baldascini, Stéphane Richard _ and Noel F. Lowndes

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Oncotarget. 2018; 9:15915-15930. https://doi.org/10.18632/oncotarget.24636

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Abstract

Murilo T.D. Bueno1,2,3,*, Marta Baldascini4,*, Stéphane Richard1,2,3 and Noel F. Lowndes4

1Segal Cancer Center, Sir Mortimer B Davis Jewish General Hospital, Lady Davis Institute for Medical Research, Montréal, Québec, Canada

2Department of Medicine, McGill University, Montréal, Québec, Canada

3Department of Oncology, McGill University, Montréal, Québec, Canada

4Genome Stability Laboratory, Centre for Chromosome Biology, National University of Ireland, Galway, Ireland

*These authors have contributed equally to this work

Correspondence to:

Stéphane Richard, email: [email protected]

Noel F. Lowndes, email: [email protected]

Keywords: DNA double strand break repair; genome stability; KDM2A; 53BP1; ubiquitin

Received: November 26, 2017 Accepted: February 27, 2018 Published: March 23, 2018

ABSTRACT

Lysine demethylase 2A (KDM2A) functions in transcription as a demethylase of lysine 36 on histone H3. Herein, we characterise a role for KDM2A in the DNA damage response in which KDM2A stimulates conjugation of ubiquitin to 53BP1. Impaired KDM2A-mediated ubiquitination negatively affects the recruitment of 53BP1 to DSBs. Notably, we show that KDM2A itself is recruited to DSBs in a process that depends on its demethylase activity and zinc finger domain. Moreover, we show that KDM2A plays an important role in ensuring genomic stability upon DNA damage. Depletion of KDM2A or disruption of its zinc finger domain results in the accumulation of micronuclei following ionizing radiation (IR) treatment. In addition, IR-treated cells depleted of KDM2A display premature exit from the G2/M checkpoint. Interestingly, loss of the zinc finger domain also resulted in 53BP1 focal distribution in condensed mitotic chromosomes. Overall, our data indicates that KDM2A plays an important role in modulating the recruitment of 53BP1 to DNA breaks and is crucial for the preservation of genome integrity following DNA damage.

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Research Papers:

Recruitment of lysine demethylase 2A to DNA double strand breaks and its interaction with 53BP1 ensures genome stability

Abstract