Senescence/SASP..

Severe DNA damage(such from 10Gy radiation) induce persistent DNA damage signal. Un-resolved foci of 53BP1 from DSB, Persistent DNA Damage Foci(PDDF), seems to be correlated with ATM DNA damage signaling pathway.

Formation of PDDF is associated with IL-6 secretion. p16 induced senescence which show control-level PDDF did not increase secretion of IL-6

Short telomere formed through replication induces senescence. However, PDDF and IL-6 secretion increment is induced before cells became fully senescent.

R-BrdU/G-53BP1 R-BrdU/G-IL-6 C: PD35 cells. R-BrdU/G-IL-6 PDDF formation(b) and IL-6 secretion(c) is increased before senescence, as graph(a) indicates.

(e) Reversion of telomere shortening by introduction of hTERT block increment of PDDF and IL-6 secretion. (f) However, DNA damage induced by 10Gy radiation show increased PDDF and IL-6 secretion regardless of hTERT expression.

P53 inactivation did not decreased IL-6 secretion at end point. Yet, it accelerated PDDF formation and IL-6 secretion.

Yet, reduction percentage is somewhat significant, indicating p53 inactivation induce telomeric dysfunction so that form PDDF.. *here, remember that cellular replicative senescence is p53 dependent. *compare value of IL-6 secretion with previous panels. The acceleration of PDDF formation and IL-6 secretion seems to be associated with dysfunctional telomere.(at least, partly.)

IL-6 secretion is dependent ATM regardless whether senescence is induced or replicative. Consistenetly, AT patient cell did not show IL-6 secretion increment upon 10Gy. Cells without ATR(e) showed IL-6 secretion increment.

Knock down of ATM pathway component NBS1, CHK2 also blocked IL-6 secretion increment upon both radiation and replicative senescence.

ATM is responsible for subset of SASP(Senescence Associated Secretory Phenotype) upon severe radiation induced senescence.

To link IL-6 secretion by ATM upon persistent DNA damage to clinical situation, invasive ability of T47D human breast cancer cell and level of phosphorylated ATM/ATR substrate and IL-6 in breast cancer specimen were assayed. C: conditioned media from HCA cells of described condition. -> pre : presenescent / XRA : X-ray..

Oncogene Induced Senescence can induce PDDF regardless of ATM status. However, IL-6 secretion upon senescence is ATM-dependent.

SASP not so related with p53.

Thank you