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.
Highlights
Lysine demethylase 2A (KDM2A), known as JHDM1A/FBXL11, was the first Jumonji C (JmjC)domain-containing histone demethylase to be identified [1]
Consistent with these novel findings, we report that KDM2A plays an important role in the mechanisms www.oncotarget.com www.oncotarget.com involved in DNA damage repair and maintenance of genome stability
Our data demonstrates that KDM2A interacts with 53BP1 via a process predominantly mediated by the zinc finger domain of KDM2A, which is reminiscent of the reported association between RAD18 and 53BP1 [14]
Summary
Lysine demethylase 2A (KDM2A), known as JHDM1A/FBXL11, was the first Jumonji C (JmjC)domain-containing histone demethylase to be identified [1]. KDM2A contains a CXXCtype zinc finger domain, a PHD domain, one F-box domain and numerous C-terminal leucine-rich repeats. The accumulation of 53BP1 at DSBs relies on the recognition of ubiquitinated Lys on histone 2A (H2AK15ub) and dimethylated Lys on histone 4 (H4K20me2)[8, 9]. These histone marks are recognized by 53BP1 through its tandem tudor www.oncotarget.com domain [9] and ubiquitylation-dependent recruitment (UDR) motif, respectively
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