SUV39H1 downregulation induces deheterochromatinization of satellite regions and senescence after exposure to ionizing radiation

Abstract

While the majority of cancer patients are exposed to ionizing radiation during diagnostic and therapeutic procedures, age-dependent differences in radiation sensitivity are not yet well understood. Radiation sensitivity is characterized by the appearance of side effects to radiation therapy, such as secondary malignancies, developmental deficits, and compromised immune function. However, the knowledge of the molecular mechanisms that trigger these side effects is incomplete. Here we used an in vitro system and showed that low-senescent normal human diploid fibroblasts (WI-38) senesce in response to 5 Gy IR, while highly senescent cultures do not show changes in cell cycle regulation and only a slight increase in the percentage of senescent cells. Our study shows that this is associated with changes in the expression of genes responsible for cell cycle progression, apoptosis, DNA repair, and aging, as well as transcriptional and epigenetic regulators. Furthermore, we propose a role of the downregulation of SUV39H1 expression, a histone methyltransferase that specifically trimethylates H3K9, and the corresponding reduction in H3K9me3 levels in the establishment of IR-induced senescence.

The Ubiquitin-like with PHD and Ring Finger Domains 1 (UHRF1)/DNA Methyltransferase 1 (DNMT1) Axis Is a Primary Regulator of Cell Senescence

“…Chk1 recruits DNMT1 to DNA damage sites (25) and directs both senescence and mitotic catastrophe in HCT116 human colorectal cancer cells (26). SUV39H1 specifically interacts with both Dnmt1 and Dnmt3a in vitro (27), and SUV39H1 downregulation is involved in senescence induced by ionizing radiation (28). Heterochromatin protein 1␣ (HP1␣) is encoded from the CBX5 gene and specifically localizes to pericentric heterochromatin sites, whereas HP1␤ and HP1␥ localize to both heterochromatic and euchromatic sites (29) and interact with DNA methyltransferase (27).…”

Copy Number Variation of Human Satellite III (1q12) With Aging

“…Large-scale distension or “unraveling” of peri/centromeric satellites occurs in all examined models of human and mouse senescence (Enukashvily et al, 2007; Swanson et al, 2013). Some results indicate that satellite CNVs contribute to the genetic component of human longevity (Sidler et al, 2014; Nygaard et al, 2016; Zhao et al, 2018). Although whole-genome sequencing may help to identify CNVs, most analytical methods suffer from limited capacity, especially in low-mappability regions (Monlong et al, 2018).…”

Postovulatory aging affects dynamics of mRNA, expression and localization of maternal effect proteins, spindle integrity and pericentromeric proteins in mouse oocytes

“…Histone H3K9 deacetylation on maternal chromatin is followed by its trimethylation during oogenesis ( Peters et al , 2001 ; Grewal and Jia, 2007 ). Subsequent recruitment of heterochromatin protein 1, alpha thalassemia/mental retardation syndrome X-linked (ATRX) chromatin remodeling factor and Aurora Kinases is a crucial process after resumption of meiosis I to form a bipolar spindle ( Muramatsu et al , 2013 ; Trapphoff et al , 2013 ; Sidler et al , 2014 ).…”