PKN1-mediated phosphorylation of histone H3 threonine residue T12 (also labeled in literature as Thr11) enables demethylation of histone H3 lysine K10 (also labeled in literature as K9) by demethylase KDM1A (LSD1) (Metzger et al. 2008). KDM1A acts on dimethylated and monomethylated H3K9 at AR-regulated promoters (Metzger et al. 2005), so it is shown that demethylation of dimethylated H3K9 (Me2K-10-H3) by KDM1A happens after demethylation of trimethylated H3K9 (Me3K-10-H3) by KDM4C (JMJD2C).
All characterized lysine demethylases other than KDM1A belong to the jumonjiC domain (JmjC) containing family.The JmjC KDMs are members of the Cupin superfamily of mononuclear Fe (II) dependent oxygenases, which are characterized by the presence of a double-stranded beta-helix core fold. The JmjC KDMs require 2 oxoglutarate (2 OG) and molecular oxygen as co substrates, producing, along with formaldehyde, succinate and carbon dioxide. This hydroxylation based mechanism does not require a protonatable lysine epsilon-amine group and consequently JmjC containing demethylases are able to catalyse demethylateion of tri , di and monomethylated lysines.
KDM3A (JHDM2A), KDM3B (JHDM2B), KDM7A (JHDM1D), PHF8 (JHDM1E) and PHF2 when complexed with ARID5B (Wen et al. 2010, Baba et al. 2011) are specific for mono or di-methylated lysine-10 on histone H3 (H3K9Me1/2) (Yamane et al. 2006, Kim et al. 2012, Horton et al. 2010, Huang et al. 2010, Loenarz et al. 2008, Feng et al. 2010, Fortschegger et al. 2010, Qi et al. 2010).
RNF8 and RNF168 polyubiquitinate KDM4A and KDM4B via ubiquitin lysine K48 cross-linking, leading to dissociation of ubiquitinated KDM4A and KDM4B from H4K20Me2 (Me2-K21-HIST1H4A) and subsequent proteasome-mediated degradation of KDM4A and KDM4B (Mallette et al. 2012).
RNF8- and RNF168-mediated removal of KDM4A and KDM4B from H4K20Me2 (Me2-K21-HIST1H4A) enables TP53BP1 (53BP1) recruitment to WHSC1-methylated histone H4K20Me2 at DNA double-strand breaks (DSBs) (Pei et al. 2011, Mallette et al. 2012)
Histone demethylases KDM4A (JMJD2A) and KDM4B (JMJD2B) bind H4K20Me2 (Me2-K21-HIST1H4A) with a higher affinity than TP53BP1 (53BP1), thereby blocking TP53BP1 recruitment to DNA double-strand breaks (DSBs). Demethylation of HIST1H4A (histone H4) by KDM4A or KDM4B is not involved in the inhibition of TP53BP1 binding (Mallette et al. 2012).
WHSC1 (MMSET) histone methyltransferase dimethylates histone H4 (HIST1H4A) on lysine residue K21 (commonly labeled in literature as K20), locally increasing the concentration of the H4K20Me2 mark. H4K20Me2 (Me2-K21-HIST1H4A) serves as a binding site for TP53BP1 (53BP1). The recruitment of WHSC1 to DNA double-strand breaks (DSBs) is independent of RNF8 and RNF168, but the catalytic activity of all three proteins is necessary for binding and accumulation of TP53BP1 at DSBs (Pei et al. 2011).