Two Superfamilies of HDACs

The very first few HDACs were identified in 1996 (Grozinger and Schreiber 2002). Since then, 18 human proteins have been established as HDACs. As listed in Table 1, known mammalian HDACs are divided into two families based on sequence similarity to yeast orthologs (Khochbin et al. 2001; Grozinger and Schreiber 2002). The first 11 members belong to the Rpd3/Hda1 (reduced potassium dependency 3/histone deacetylase 1) family, and the remaining seven are classified as members of sirtuin (S/r2-related protein) family (Sauve 2010; Verdin et al. 2010). These two families utilize different catalytic mechanisms: while the Rpd3/Hda1 family members are Zn2+-dependent enzymes (Fig. 1a), sirtuins require NAD+ as a cofactor (Fig. 1b). Dependent on how similar they are towards yeast Rpd3 and Hda1, members of the Rpd3/Hda1 family have been further grouped into three classes, I, II, and IV, leaving sirtuins also known as class III members. Historically, the 18 deacetylases were initially grouped into three classes, I, II, and III, with HDAC11 being considered a class I member. However, more thorough sequence analysis revealed ambiguity of HDAC11 between classes I and II, so a new class (IV) was created for HDAC11 and its orthologs (Gregoretti et al. 2004).

Due to historical traditional reasons, the acronym "HDAC" has been kept for mammalian members of the Rpd3/Hda1 family even though HDAC6 mainly acts in the cytoplasm to deacetylate nonhistone proteins such as a-tubulin (Hubbert et al. 2002). In addition to HDAC6, other HDACs have unique subcellular localization (Table 1). Class IIa HDACs localize to both the nucleus and cytoplasm, and their

Table 1 Characteristics of 18 human HDACs

Catalytic

Subcellular

Family

Class

Yeast homology

Member

Size (aa)

sites

localization

Rpd3/Hda1

I

Rpd3-like

HDAC1

483

1

Nuclear

HDAC2

488

1

Nuclear

HDAC3

428

1

Cytoplasmic/nuclear

HDAC8

377

1

Nuclear

IIa

Hdal-like

HDAC4

1,084

1

Cytoplasmic/nuclear

HDAC5

1,122

1

Cytoplasmic/nuclear

HDAC7

991

1

Cytoplasmic/nuclear

HDAC9

1,069

1

Cytoplasmic/nuclear

IIb

Hdal-like

HDAC6

1,215

Cytoplasmic

HDAC10

669

1

Cytoplasmic/nuclear

Rpd3- or

IV

Hda1-like

HDAC11

347

1

Cytoplasmic/nuclear

Sirtuin

III

Sir2-like

SIRT1

747

1

Nuclear

SIRT2

389

1

Nuclear/cytoplasmic

Mitochondrial/

SIRT3

399

1

nuclear

SIRT4

314

1

Mitochondrial

SIRT5

310

1

Mitochondrial

SIRT6

355

1

Nuclear

SIRT7

400

1

Nucleolar

For additional information, refer to Grozinger and Schreiber (2002), Michishita et al. (2005), Scher et al. (2007), Yang and Seto (2008b), Verdin et al. (2010). Alternative splicing often generates multiple isoforms, so in majority of cases the longest isoforms are listed here.

For additional information, refer to Grozinger and Schreiber (2002), Michishita et al. (2005), Scher et al. (2007), Yang and Seto (2008b), Verdin et al. (2010). Alternative splicing often generates multiple isoforms, so in majority of cases the longest isoforms are listed here.

cytoplasmic localization functions as an important means of regulation in response to cellular signaling. Sirtuins members, SIRT3, 4, and 5, localize to the mitochondria, whereas SIRT7 is present in nucleoli (Michishita et al. 2005). Consistent with this, the former three sirtuins play a role in mitochondrial metabolism, and while SIRT7 is known to regulate RNA polymerase I-dependent transcription (Verdin et al. 2010). Within the nucleus, HDAC1, 2, and 3 are catalytic subunits of stable multiprotein complexes, and some of the noncatalytic subunits serve to regulate the deacetylase activity (Grozinger and Schreiber 2002; Yang and Seto 2008b). This is also a common theme for many chromatin-modifying enzymes, such as some of the aforementioned acetyltransferases (e.g., HAT1, GCN5, ATAC2, and MYST family members) (Table 1).

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