finger 20), a protein that regulates p53 and NF-κB transcription factors in a lysine
methylation-dependent manner [109, 110]. The association of PHF20 with methylated p53 stabilizes p53 by limiting Mdm2-mediated ubiquitylation and subsequent
degradation of p53 [109]. PHF20 is also involved in transcriptional regulation and
activates p53 through binding the p53 promoter [111, 112]. PHF20 was also recently
shown to be necessary for somatic cell reprogramming to generate inducible
pluripotent stem cells [113]. In the NF-κB pathway, PHF20 was shown to drive
the constitutive activation of this transcription factor in gliomas by preventing the
interaction between protein phosphatase PP2A and the p65 subunit of NF-κB. This
process strictly depends on the recognition of a methyllysine in p65 (Lys218 or
Lys221) by PHF20-Tudor2 [110], suggesting that inhibiting this interaction
might be beneficial for cancer treatment.
4.3.2 Tandem Tudor Domains (53BP1, SGF29, SHH1, UHRF1,
Spindlin-1)
4.3.2.1 Structure and Function
Tandem Tudor domains were first identified in p53-binding protein 1 (53BP1)
[97, 114], a protein that has recently emerged as a major regulator of DNA
double-strand break (DSB) repair by nonhomologous end joining (NHEJ) [115]
and as an essential protein in the protection against breast cancer due to its ability
to contribute significantly to the tumor suppression pathways associated with
DNA repair, cell cycle control, apoptosis, and cell senescence [116]. 53BP1 recruits
the NHEJ effector protein RIF1 (Rap1-interacting factor 1) to DSBs [117, 118].
53BP1 is essential for class switch recombination in antibody diversification [119]
and for the fusion of deprotected telomeres [120], two processes that depend on
NHEJ. Furthermore, 53BP1 inactivates homologous recombination (HR)-mediated
DNA repair by inhibiting DNA end resection, the initial step of HR [121]. Remarkably, deletion of the 53bp1 gene restores HR in cells defective in HR protein BRCA1
and alleviates embryonic lethality in Brca1-nullizygous mice [121].
Another TT-containing protein is SAGA-associated factor 29 (SGF29), a subunit
of Spt-Ada-Gcn5 acetyltransferase (SAGA) chromatin-modifying complex that
regulates gene expression [122]. SAGA is evolutionarily conserved and was initially
identified in budding yeast where it was shown to acetylate and deubiquitylate
histones [56, 123]. The SGF29 subunit is required for the recruitment of SAGA to
gene promoters and for the acetylation of histone H3 by SAGA [57]. In human
and Saccharomyces cerevisiae, SGF29 recognizes histone marks H3K4me2 and
H3K4me3, with a slight preference for H3K4me3, by means of tandem Tudor
domains (SGF29-TT) [57, 124]. The structures of budding yeast and human
SGF29-TT are virtually identical [57]. Both yeast and human SGF29 are highly
specific for the H3 sequence surrounding Lys4. The affinity of SGF29-TT for its
target peptide is higher than the affinity of 53BP1-TT for H4K20me2. Unlike
53BP1, SGF29 does not have a stringent methylation-state specificity. SGF29-TT
Methyl-Readers and Inhibitors
357
methylation-dependent manner [109, 110]. The association of PHF20 with methylated p53 stabilizes p53 by limiting Mdm2-mediated ubiquitylation and subsequent
degradation of p53 [109]. PHF20 is also involved in transcriptional regulation and
activates p53 through binding the p53 promoter [111, 112]. PHF20 was also recently
shown to be necessary for somatic cell reprogramming to generate inducible
pluripotent stem cells [113]. In the NF-κB pathway, PHF20 was shown to drive
the constitutive activation of this transcription factor in gliomas by preventing the
interaction between protein phosphatase PP2A and the p65 subunit of NF-κB. This
process strictly depends on the recognition of a methyllysine in p65 (Lys218 or
Lys221) by PHF20-Tudor2 [110], suggesting that inhibiting this interaction
might be beneficial for cancer treatment.
4.3.2 Tandem Tudor Domains (53BP1, SGF29, SHH1, UHRF1,
Spindlin-1)
4.3.2.1 Structure and Function
Tandem Tudor domains were first identified in p53-binding protein 1 (53BP1)
[97, 114], a protein that has recently emerged as a major regulator of DNA
double-strand break (DSB) repair by nonhomologous end joining (NHEJ) [115]
and as an essential protein in the protection against breast cancer due to its ability
to contribute significantly to the tumor suppression pathways associated with
DNA repair, cell cycle control, apoptosis, and cell senescence [116]. 53BP1 recruits
the NHEJ effector protein RIF1 (Rap1-interacting factor 1) to DSBs [117, 118].
53BP1 is essential for class switch recombination in antibody diversification [119]
and for the fusion of deprotected telomeres [120], two processes that depend on
NHEJ. Furthermore, 53BP1 inactivates homologous recombination (HR)-mediated
DNA repair by inhibiting DNA end resection, the initial step of HR [121]. Remarkably, deletion of the 53bp1 gene restores HR in cells defective in HR protein BRCA1
and alleviates embryonic lethality in Brca1-nullizygous mice [121].
Another TT-containing protein is SAGA-associated factor 29 (SGF29), a subunit
of Spt-Ada-Gcn5 acetyltransferase (SAGA) chromatin-modifying complex that
regulates gene expression [122]. SAGA is evolutionarily conserved and was initially
identified in budding yeast where it was shown to acetylate and deubiquitylate
histones [56, 123]. The SGF29 subunit is required for the recruitment of SAGA to
gene promoters and for the acetylation of histone H3 by SAGA [57]. In human
and Saccharomyces cerevisiae, SGF29 recognizes histone marks H3K4me2 and
H3K4me3, with a slight preference for H3K4me3, by means of tandem Tudor
domains (SGF29-TT) [57, 124]. The structures of budding yeast and human
SGF29-TT are virtually identical [57]. Both yeast and human SGF29 are highly
specific for the H3 sequence surrounding Lys4. The affinity of SGF29-TT for its
target peptide is higher than the affinity of 53BP1-TT for H4K20me2. Unlike
53BP1, SGF29 does not have a stringent methylation-state specificity. SGF29-TT
Methyl-Readers and Inhibitors
357