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Heterochromatin formation and remodeling by IRTKS condensates counteract cellular senescence

ABSTRACT: Heterochromatin, a key component of the eukaryotic nucleus, is fundamental to the regulation of genome stability, gene expression and cellular functions. However, the factors and mechanisms involved in heterochromatin formation and maintenance still remain largely unknown. Here, we show that insulin receptor tyrosine kinase substrate (IRTKS), an I-BAR domain protein, is indispensable for constitutive heterochromatin formation via liquid‒liquid phase separation (LLPS). In particular, IRTKS droplets can infiltrate heterochromatin condensates composed of HP1 and diverse DNA-bound nucleosomes. IRKTS can stabilize HP1 by recruiting the E2 ligase Ubc9 to SUMOylate HP1 which enables it to form larger phase-separated droplets than unmodified HP1. Furthermore, IRTKS deficiency leads to loss of heterochromatin, resulting in genome-wide changes in chromatin accessibility and aberrant transcription of repetitive DNA elements. This leads to activation of cGAS-STING pathway and type-I interferon (IFN-I) signaling, as well as to the induction of cellular senescence and senescence-associated secretory phenotype (SASP) responses. Collectively, our findings establish a mechanism by which IRTKS condensates consolidate constitutive heterochromatin, revealing an unexpected role of IRTKS as an epigenetic mediator of cellular senescence.

SUBMITTER: Prof. Zeguang Han

PROVIDER: S-SCDT-10_1038-S44318-024-00212-3 | biostudies-other |

REPOSITORIES: biostudies-other

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