Table 1 SETD8 roles in physiological and pathological pathways

Cell cycle progression

A direct role in the regulation of ORIs

[44]

Upregulated in G2/M and early G1, nearly absent in S phase

[17, 20, 35–40]

SETD8 ubiquitin-mediated degradation is required for the onset of S phase

[34, 36–42]

Transcriptional regulation

Promotes transcriptional repression

[31, 42, 55–57]

Mediates transcriptional activation

[20, 45, 52–54]

Regulation of DNA replication

Binds to the H4 N-terminal tail and blocks the acetylation of H4K5, H4K8 and H4K12 during G1, hindering DNA replication

[41]

DNA damage response

SETD8 methyltransferase activity during the DNA damage response is necessary to recruit 53BP1 for efficient DNA repair and checkpoint activation; enzyme depletion leads to an increase in spontaneous DNA damage

[18, 20, 49]

Regulation of p53 activity

Catalyzes p53 monomethylation (p53K382me1), suppressing p53-dependent transcription activation in cancer cells

[26]

Methylates Numb (K158 and K163), thus uncoupling it from p53 and increasing p53 ubiquitination and degradation

[27]

Regulation of PCNA

Monomethylates PCNA (PCNAK248me1), thus stabilizing PCNA proteins through inhibition of polyubiquitylation and enhancing the interaction between PCNA and the flap endonuclease FEN1

[28]

Cancer

Overexpressed in different types of cancer tissues and cancer cell lines including bladder cancer, non-small cell and small cell lung carcinoma, chronic myelogenous leukemia, hepatocellular carcinoma, and pancreatic cancer

[28]

SETD8-mediated p53K382me1 suppresses p53-dependent transcription activation in cancer cells

[26]

SETD8-dependent monomethylation of PCNAK248 promote tumorigenesis

[28]

Implicated in cancer invasiveness and metastasis through its interaction with TWIST

[60]

Direct target of miRNA miR-127-3p, influencing OS progression and metastasis

[62]

Reduced SETD8 expression by polymorphism rs16917496 T > C is associated with decreased susceptibility to different types of cancer (breast and ovarian cancer, SCLC, hepatocellular carcinoma, NSCLC, childhood ALL)

[63–68]

miR-7-promoted SETD8 mRNA degradation inhibits H4K20 monomethylation and suppresses EMT and invasion of breast cancer cells

[61]

Crucial for AR-mediated transcription activation of PSA gene

[69]

SETD8 binding interaction is required for PRDM2 tumor suppressor function

[70]

Regulation of erythroid cells maturation

SETD8 is a repressor of endothelial transcription factor GATA-2 expression and regulates erythroid maturation and promotes the maturation and survival of definitive erythroblasts

[72–74]

Maintenance of adult skin

Loss of SETD8 results in loss of proliferation and impaired differentiation, accompanied by loss of the interfollicular epidermis and sebaceous glands

[75]

Regulation of adipogenesis

Upregulation of Setd8 gene by PPARγ promotes adipogenesis, while gene knockdown suppresses it

[52]

Neurodevelopmental disorders

IUGR induces a reduction of PPARγ-SETD8-H4K20me1 and Wnt signaling, thus causing impaired neurodevelopment and subsequent neurocognitive impairment

[76]