CK2 Regulates The Mechanism Of Heterochromatin DNA Damage Response In Premature Cells

Aging is a process of gradual loss of physiological function,mainly manifested as self-repairing ability declined and irreversible growth stagnation at the cellular level.The main causes of aging include DNA damage accumulation,telomere shortening and INK4 a / ARF activation and so on.Hutchinson Gilford progeria syndrome(HGPS)is an important model for studying senescence mechanism which is caused by a de novo G608 G mutation in LMNA gene,resulting in a 50-aa internal deletion(Δ50)in prelamin A that contains a proteolytic cleavage site required for premature lamin A.Heterochromatin Protein 1(HP1)is an important component to maintain heterochromatin formation and has been found to regulate ATM-KAP-1-mediated DNA damage repair pathway in recent years.Casein Kinase 2(CK2)is a conserved serine/threonine protein kinase which is widely distributed in eukaryotes and regulates cell signaling,survival,senescence and apoptosis.Our previous studies have shown that Zmpste24-deficient cells have a significantly lower and delayed HP1αT50 phosphorylation level than wild-type cells after DNA damage.Furthermore,using siRNA to interfere with HP1α protein can improve the response to DNA damage in Zmpste24-deficient cells.On the basis of this finds,we used Zmpste24-deficient mouse model as the research object to explore the function of protein kinase CK2 on HP1α-mediated DNA damage repair signal mechanism.The main results are as follows: 1.Mutation at HP1αT50 site will affect the response of DNA damage in heterochromatin;2.CK2 is the key kinase that regulates phosphorylation of HP1αT50 site;3.The nuclear lamina protein Lamin A interacts with CK2 and mediates its involvement in heterochromatin DNA damage responses;4.In Zmpste24-deficient cells,CK2 enzyme activity was decreased,leading to DNA damage accumulation;5.Small molecule TBB(4,5,6,7-tetrabromobenzotrizole)inhibits CK2 enzyme activity,can lead to defect of DNA damage response and promote cell apoptosis in premature cells.In summary,we conclude that:1.lamin A-CK2α-HP1α pathway is involved in DNA damage response process in premature aging cells.2.Inhibiting the activity of CK2 in premature aging cells can lead to rise apoptosis levels and decrease the expression of the senescence marker P16.Therefore,according to the results of this study,it is suggested that inhibition of CK2 activity in premature aging cells can impaire the DNA damage response process of lamin A-CK2α-HP1α pathway,leading to accumulation of DNA damage and accelerate the apoptosis of aging cells.This mechanism is conducive to the removal of aging cells,so as to achieve the purpose of anti-aging.