A number of studies in the past few years reveal diverse biological roles of the
PHD fingers. They recognize unmodified and modified histone H3 tails, interact with
nonhistone proteins, and associate with DNA [25, 26], the specificity of binding
being dictated by the properties of the particular pocket [4]. Some proteins contain
only one canonical PHD finger, but some harbor several PHD fingers that act in
concert or have independent functions. The PHD finger can be linked to a zinc
knuckle, a zinc finger that coordinates one zinc ion, and is characterized by either C4
or C2HC sequence. The closely coupled tandem PHD fingers create a distinct fold,
the double PHD finger (DPF), whereas two PHD fingers connected by a zinc knuckle
are assembled into the PZP (PHD-zinc knuckle-PHD) domain. The various combinations of coupled modules greatly influence the overall function and dynamics of
the PHD finger. The biological activity of the PHD finger can be further altered
through the action of adjacent domains, such as histone readers (bromodomain,
chromodomain, Tudor, etc.) or catalytic PTM writers, and erasers.
One of the well-established subsets of PHD fingers, exemplified by the PHD
fingers of BPTF and ING2 [27–30], consists of numerous proteins that have been
shown to bind H3K4me3 with high specificity and affinity. The lysine-specific
demethylases JARID1A (KDM5A) and JARID1B (KDM5B) also has the ability
to bind H3K4me3 via their three PHD finger domains [31, 32].
A smaller number of PHD fingers display a preference for the H3K9me3 [33–37].
The ADD (ATRX-DNMT3-DNMT3L) domain is a methyllysine-binding domain
that has been characterized in the DNA methyltransferases DNMT3A, DNMT3B,
and DNMT3L family and the chromatin remodeler ATRX. The increased prevalence
of ATRX loss-of-function mutations in various forms of cancer suggests that it plays
an essential role in regard to proper chromatin structure and/or gene regulation in
these tissues; however, our overall understanding of both the normal and oncogenic
roles of the ATRX ADD domain is still evolving. In addition to cancer, missense
mutations in the ATRX ADD domain account for approximately 50% of patients
with ATRX syndrome, a congenital disorder that causes intellectual disabilities [38].
In addition to recognizing histone tails, PHD fingers have been implicated in
binding to nonhistone proteins and self-association. For example, the third PHD
finger (PHD3) of MLL1 is capable of binding both H3K4me3 and the nuclear
cyclophilin Cyp33, while the second PHD finger (PHD2) of MLL1 forms a dimer
and shows E3 ubiquitin ligase activity in the presence of the E2-conjugating enzyme
CDC34 [39]. The mechanistic outcome of histone or nonhistone recognition by PHD
fingers is the recruitment or stabilization of their host proteins, i.e., transcription
factors, PTM writing and erasing and nucleosome-remodeling enzymes, and other
elements of the epigenetic machinery, at chromatin. Yet, the physiological consequence of these interactions is highly context-dependent and is often determined by
the overall function of the chromatin-modifying complex in which the PHD finger
resides.
Disrupting PHD fingers from properly reading their histone marks has been
implicated in a wide variety of human disorders [40]. Mutation, translocation, or
344
G. Sbardella
PHD fingers. They recognize unmodified and modified histone H3 tails, interact with
nonhistone proteins, and associate with DNA [25, 26], the specificity of binding
being dictated by the properties of the particular pocket [4]. Some proteins contain
only one canonical PHD finger, but some harbor several PHD fingers that act in
concert or have independent functions. The PHD finger can be linked to a zinc
knuckle, a zinc finger that coordinates one zinc ion, and is characterized by either C4
or C2HC sequence. The closely coupled tandem PHD fingers create a distinct fold,
the double PHD finger (DPF), whereas two PHD fingers connected by a zinc knuckle
are assembled into the PZP (PHD-zinc knuckle-PHD) domain. The various combinations of coupled modules greatly influence the overall function and dynamics of
the PHD finger. The biological activity of the PHD finger can be further altered
through the action of adjacent domains, such as histone readers (bromodomain,
chromodomain, Tudor, etc.) or catalytic PTM writers, and erasers.
One of the well-established subsets of PHD fingers, exemplified by the PHD
fingers of BPTF and ING2 [27–30], consists of numerous proteins that have been
shown to bind H3K4me3 with high specificity and affinity. The lysine-specific
demethylases JARID1A (KDM5A) and JARID1B (KDM5B) also has the ability
to bind H3K4me3 via their three PHD finger domains [31, 32].
A smaller number of PHD fingers display a preference for the H3K9me3 [33–37].
The ADD (ATRX-DNMT3-DNMT3L) domain is a methyllysine-binding domain
that has been characterized in the DNA methyltransferases DNMT3A, DNMT3B,
and DNMT3L family and the chromatin remodeler ATRX. The increased prevalence
of ATRX loss-of-function mutations in various forms of cancer suggests that it plays
an essential role in regard to proper chromatin structure and/or gene regulation in
these tissues; however, our overall understanding of both the normal and oncogenic
roles of the ATRX ADD domain is still evolving. In addition to cancer, missense
mutations in the ATRX ADD domain account for approximately 50% of patients
with ATRX syndrome, a congenital disorder that causes intellectual disabilities [38].
In addition to recognizing histone tails, PHD fingers have been implicated in
binding to nonhistone proteins and self-association. For example, the third PHD
finger (PHD3) of MLL1 is capable of binding both H3K4me3 and the nuclear
cyclophilin Cyp33, while the second PHD finger (PHD2) of MLL1 forms a dimer
and shows E3 ubiquitin ligase activity in the presence of the E2-conjugating enzyme
CDC34 [39]. The mechanistic outcome of histone or nonhistone recognition by PHD
fingers is the recruitment or stabilization of their host proteins, i.e., transcription
factors, PTM writing and erasing and nucleosome-remodeling enzymes, and other
elements of the epigenetic machinery, at chromatin. Yet, the physiological consequence of these interactions is highly context-dependent and is often determined by
the overall function of the chromatin-modifying complex in which the PHD finger
resides.
Disrupting PHD fingers from properly reading their histone marks has been
implicated in a wide variety of human disorders [40]. Mutation, translocation, or
344
G. Sbardella