Evidence that Tip60 Induces the DDR & Cardiomyocyte Replicative Senescence in the Neonatal Heart

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Tip60 (Tat interactive protein, 60 kD) is a tumor suppressor protein that acetylates histone and non‐histone proteins. Among the latter, ATM (Ataxia Telangiectasia Mutated), a kinase that induces the DNA damage response (DDR), is activated in cancer cells by Tip60‐mediated acetylation. We are investigating the function of Tip60 in the heart, using global and conditional knockout mouse models to disrupt the Kat5 gene encoding Tip60. Because global knockout (i.e. Tip60−/−) causes early embryonic lethality, we used Tip60+/− heterozygotes to show that, when under cardiac stress, modest Tip60 depletion correlates with re‐activation of the cardiomyocyte (CM) cell‐cycle in the adult heart. More recently, using a knockout model wherein Tip60 is constitutively and specifically depleted in CMs, we observed CM dropout and lethality in three‐month‐old mice, wherein hearts exhibited features of mitotic catastrophe. Because the latter phenotype was preceded by increased CM density, it was suggested that Tip60‐depletion may extend the duration of CM proliferation during neonatal stages of heart development. Moreover, considered in the context of recent reports that ATM is activated at birth to induce the DDR, which in turn causes replicative senescence of CMs by mid‐neonatal stages, these findings suggest that Tip60 induces these events. To examine these possibilities we are conditionally depleting Tip60 in CMs of Tip60F/F;Cre neonatal mice by injecting tamoxifen at postnatal day 0 (P0). To date, immunostaining of sections from neonatal hearts with antibodies that recognize 5′‐BrdU, phospho‐histone‐H3, and phospho‐ATM (pATM) has revealed that Tip60 depletion significantly increases CM proliferation as early as P7, by which time CM proliferation is normally diminished, and that this is accompanied by significantly decreased pATM levels, indicative of a diminished DDR. These findings provide further support for the notion that DDR activation at the time of birth induces replicative senescence of neonatal CMs, implicating Tip60 as the inducer of this process.Support or Funding InformationNIH HL131788 (JL & JA), and a grant from the MCW Cardiovascular CenterThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.