Figure 2.

SIRT6 inhibits genomic and telomeric instability. SIRT6 binds to the 5’-untranslated region (UTR) of LINE1 loci and mono-ADP-ribosylates KAP1, which promotes the interaction between KAP1 and HP1α, leading to LINE1 elements packaging into transcriptionally silent heterochromatin. In contrast, loss of SIRT6 in the 5’-UTR of LINE1 elevates LINE1 activity. Accumulation of cytoplasmic LINE1 cDNA instigates chromosomal rearrangements and provokes a strong type I interferon response and subsequent inflammation through the cytoplasmic DNA sensor cGAS. Impaired telomeres upregulate p53 expression, which activates miR-26, thereby decreasing SIRT6 content. During the S phase, SIRT6 deacetylates telomeric H3K9, enabling the efficient binding of the WRN protein to telomeres, leading to the recruitment of telomere/shelterin protein complexes to protect telomere integrity. In response to oxidative stress, SIRT6 recruits SNF2H to damaged telomeres to promote chromatin relaxation, which is associated with the maintenance of telomeres. In addition, SIRT6-mediated deacetylation of H3K18 within pericentric satellite sequences favors the retention of KAP1, repressing satellite transcription and maintaining proper chromosome segregation in mitosis.