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Table 1 SETD8 roles in physiological and pathological pathways

From: The emerging role of lysine methyltransferase SETD8 in human diseases

Physiological/pathological pathways Roles of SETD8 References
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, 3540]
SETD8 ubiquitin-mediated degradation is required for the onset of S phase [34, 3642]
Transcriptional regulation Promotes transcriptional repression [31, 42, 5557]
Mediates transcriptional activation [20, 45, 5254]
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) [6368]
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 [7274]
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]