Subsequently, on the base of its homology to MOZ, another MYST member called
MORF was discovered [28, 29]. In cells, MOZ and MORF form similar stable protein
complexes with the ING proteins. These complexes possess a HAT activity specific
for histone H3 and can function as transcriptional coactivators. The HAT activity of
MOZ/MORF complexes is required for normal developmental programmes, including haematopoiesis and skeletogenesis, and for the regulation of various genes,
especially the Hox family [19, 30–33]. HBO1 was discovered in a two-hybrid
screening looking for new interactor of ORC1, the subunit of the origin recognition
complex (ORC) [34]. HBO1 is a major mediator of both histone H3 (K14, K23) and
H4 (K5, K8, K12) acetylation. As for other MYST members, the specificity of histone
tail modification is finely controlled by the different scaffold subunits of HBO1
complex: for example, JADE proteins are required for H4 acetylation, while the
HBO1 complex at the H3 contains BRPF (bromodomain- and PHD finger-containing
protein 1) protein [35].
Finally, the basal transcription factor family and the nuclear receptor cofactors
family are classified as HATs; nevertheless both these families do not harbour
acetylation-related structural motifs. The transcription factor-related HATs include
TATA box binding protein (TBP)-associated factor TAFII250 and TFIIIC. Nuclear
receptor cofactors family include steroid receptor coactivator-1 (SRC-1), steroid
receptor coactivator-3/activated in breast cancer-1 (SRC-3/AIB-1), thyroid hormone
receptor activator molecule-1 (TRAM-1), nuclear receptor coactivator-3 (NCOA-3)
and transcriptional intermediary factor-2 (TIF-2).
More recently, a new family lacking canonical features of known HATs, being
relatively smaller in size, and other associated domains has been identified. This new
family has been named Camello protein family and includes functional HATs that
show specificity towards histone H4, exhibit perinuclear localization and are essential for zebrafish development [36].
3 HAT and Cancer
Abnormal acetylation patterns can be the result of genetic lesions (e.g. haploinsufficiency
or inactivating mutations, resulting in the silencing of target genes), but also of an
enhanced HAT activity on the wrong targets (e.g. oncogenes), due to their aberrant
recruitment or overexpression. Hence, HAT genetic alterations as well as HAT functional
dysregulation are strongly linked to human diseases, in particular to cancer [8]. As
mentioned above, alterations of protein acetylation impact on different hallmarks of
cancer such as cell motility and invasion, cell cycle, senescence, cell death, differentiation, DNA repair and DNA damage response; thus both hyperacetylation and
hypoacetylation can cooperate with other cancerous modifications to promote tumorigenesis and tumour progression (Fig. 2). To date, the genetic alterations of HATs as well
as of the opposing enzymes HDACs are reported to be involved in the expression of
Histone Acetyltransferase Enzymes: From Biological Implications to Most. . .
99
MORF was discovered [28, 29]. In cells, MOZ and MORF form similar stable protein
complexes with the ING proteins. These complexes possess a HAT activity specific
for histone H3 and can function as transcriptional coactivators. The HAT activity of
MOZ/MORF complexes is required for normal developmental programmes, including haematopoiesis and skeletogenesis, and for the regulation of various genes,
especially the Hox family [19, 30–33]. HBO1 was discovered in a two-hybrid
screening looking for new interactor of ORC1, the subunit of the origin recognition
complex (ORC) [34]. HBO1 is a major mediator of both histone H3 (K14, K23) and
H4 (K5, K8, K12) acetylation. As for other MYST members, the specificity of histone
tail modification is finely controlled by the different scaffold subunits of HBO1
complex: for example, JADE proteins are required for H4 acetylation, while the
HBO1 complex at the H3 contains BRPF (bromodomain- and PHD finger-containing
protein 1) protein [35].
Finally, the basal transcription factor family and the nuclear receptor cofactors
family are classified as HATs; nevertheless both these families do not harbour
acetylation-related structural motifs. The transcription factor-related HATs include
TATA box binding protein (TBP)-associated factor TAFII250 and TFIIIC. Nuclear
receptor cofactors family include steroid receptor coactivator-1 (SRC-1), steroid
receptor coactivator-3/activated in breast cancer-1 (SRC-3/AIB-1), thyroid hormone
receptor activator molecule-1 (TRAM-1), nuclear receptor coactivator-3 (NCOA-3)
and transcriptional intermediary factor-2 (TIF-2).
More recently, a new family lacking canonical features of known HATs, being
relatively smaller in size, and other associated domains has been identified. This new
family has been named Camello protein family and includes functional HATs that
show specificity towards histone H4, exhibit perinuclear localization and are essential for zebrafish development [36].
3 HAT and Cancer
Abnormal acetylation patterns can be the result of genetic lesions (e.g. haploinsufficiency
or inactivating mutations, resulting in the silencing of target genes), but also of an
enhanced HAT activity on the wrong targets (e.g. oncogenes), due to their aberrant
recruitment or overexpression. Hence, HAT genetic alterations as well as HAT functional
dysregulation are strongly linked to human diseases, in particular to cancer [8]. As
mentioned above, alterations of protein acetylation impact on different hallmarks of
cancer such as cell motility and invasion, cell cycle, senescence, cell death, differentiation, DNA repair and DNA damage response; thus both hyperacetylation and
hypoacetylation can cooperate with other cancerous modifications to promote tumorigenesis and tumour progression (Fig. 2). To date, the genetic alterations of HATs as well
as of the opposing enzymes HDACs are reported to be involved in the expression of
Histone Acetyltransferase Enzymes: From Biological Implications to Most. . .
99