Table 1 Roles for the methyltransferase SETD8 in DNA damage repair

DNA damage

Inhibition of SETD8 expression induces massive DSBs

[2, 11, 18, 40]

Inactivation of the CRL4-Cdt2-PCNA-SETD8 degradation axis leads to DNA damage

[52]

SETD8 catalyzes PCNA methylation on lysine 248 that enhances its interaction with FEN1, whereas loss of PCNA methylation induces DNA damage and makes cells more susceptible to DNA damage

[20]

The E3 ubiquitin ligases RNF168 mediates SETD8 localization to chromatin flanking DNA damage

[53]

Removal of SET8 supports the modulation of chromatin structure after DNA damage

[54]

53BP1 recruitment

H4K20me2 is a docking site for 53BP1

[33]

The SUV4-20 activity and H4K20me2/3 methylation are inessential for recruitment of 53BP1 and c-NHEJ-directed repair pathway

[55]

SETD8-mediated H4K20me1 alone is insufficient, but H4K20me2 is also required, for 53BP1 binding and the DSBs repair

[56,57,58]

53BP1 recruitment depends on H4K20me2 established prior to DNA damage rather than de novo H4K20 methylation mediated by MMSET/WHSC1, and acetylation at H4K16 inhibits 53BP1 binding to extant H4K20me2

[59]

Replication-coupled dilution of H4K20me2 guides 53BP1 to pre-replicative chromatin

[17]

SETD8 interacts with RNF8 and RNF168 in a ubiquitination-dependent manner that promotes H2A ubiquitination in response to DNA damage and 53BP1 is a reader of the DNA damage-induced H2A Lys 15 ubiquitin mark

[60, 61]

SETD8 is transiently recruited to laser-induced DNA damage sites through its interaction with PCNA, which promotes 53BP1 recruitment to the DSBs

[46]

The histone methyltransferase MMSET/WHSC1 catalyzes H4K20me2 based on SETD8-mediated H4K20me1, which facilitates 53BP1 recruitment in response to DSBs

[23]

SETD8 is functionally required for 53BP1 accumulation and for efficient repair of DSBs specifically via the NHEJ

[11]

The SETD8 inhibitor UNC-0379 blocks H4K20 methylation and reduced recruitment of the 53BP1 protein to DSBs

[55]

The methyltransferase MMSET-mediated H4K20me2 recruits the nucleotide excision repair factor XPA to DNA loci in a 53BP1-dependent manner

[24]

BRCA1 recruitment

H4K20me0 recognition is required for TONSL–MMS22L binding to chromatin and accumulation at challenged replication forks and DNA lesions

[62]

BRCA1 recruitment requires recognition of H4K20me0, linking DSB repair pathway choice directly to sister chromatid availability

[16]

BRCA1-BARD1 binds nucleosomes through recognition of both unmethylated H4K20 and H2AK15ub to promote HR-mediated DSB repair

[63]

Recognition of monoubiquitin at the N terminus of H2A by BRCA1-BARD1 promotes ubiquitylation at the C terminus of H2A, which recruits SMARCAD1 to oppose the positioning of 53BP1

[64]

RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage

[65]

Checkpoint regulation

SETD8 catalyzes p53 methylation and deletion of SETD8 arguments the checkpoint activation functions of p53

[34]

Inactivation of the CRL4-Cdt2-PCNA-SETD8 degradation axis increases expression of p53 and its transactivated proapoptotic genes

[52]

SETD8 mediates Numb methylation that uncouples Numb from p53, increasing p53 ubiquitination and degradation

[35]

SETD8 abundance regulated by SCF^b−TRCP-mediated pathways contribute to the onset of DNA damage-induced checkpoints

[6]