Abstract
The striatin-interacting phosphatase and kinase (STRIPAK) complexes integrate extracellular stimuli that result in intracellular activities. Previously, we discovered that STRIPAK is a key machinery responsible for loss of the Hippo tumor suppressor signal in cancer. Here, we identified the Hippo-STRIPAK complex as an essential player in the control of DNA double-stranded break (DSB) repair and genomic stability. Specifically, we found that the mammalian STE20-like protein kinases 1 and 2 (MST1/2), independent of classical Hippo signaling, directly phosphorylated zinc finger MYND type–containing 8 (ZMYND8) and hence resulted in the suppression of DNA repair in the nucleus. In response to genotoxic stress, the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway was determined to relay nuclear DNA damage signals to the dynamic assembly of Hippo-STRIPAK via TANK-binding kinase 1–induced (TBK1-induced) structural stabilization of the suppressor of IKBKE 1– sarcolemma membrane–associated protein (SIKE1-SLMAP) arm. As such, we found that STRIPAK-mediated MST1/2 inactivation increased the DSB repair capacity of cancer cells and endowed these cells with resistance to radio- and chemotherapy and poly(ADP-ribose)polymerase (PARP) inhibition. Importantly, targeting the STRIPAK assembly with each of 3 distinct peptide inhibitors efficiently recovered the kinase activity of MST1/2 to suppress DNA repair and resensitize cancer cells to PARP inhibitors in both animal- and patient-derived tumor models. Overall, our findings not only uncover what we believe to be a previously unrecognized role for STRIPAK in modulating DSB repair but also provide translational implications of cotargeting STRIPAK and PARP for a new type of synthetic lethality anticancer therapy.
Highlights
DNA double-stranded breaks (DSBs) constitute the most deleterious threat to genomic integrity, and the repair of DNA is essential for normal cell growth and animal development [1]
To determine whether Striatin-interacting phosphatase and kinase (STRIPAK) complexes are involved in the cellular response to DNA damage, we performed an siRNA miniscreen targeting individual components of the complexes in 2 well-characterized DSB reporter systems, to identify potential regulators, and performed a neutral comet assay to validate the roles of candidate hits in DNA repair (Figure 1A)
The inhibitory effects on DSB repair seemed to be specific for mammalian STE20-like protein kinases 1 and 2 (MST1/2) kinases, as knockdown of other kinase components of STRIPAK such as MST3, MST4, serine/threonine kinase 25 (STK25), TRAF2 and NCK interacting kinase (TNIK), MNIK1, and MAP4K4 failed to achieve such inhibition (Figure 1B and Supplemental Figure 1A)
Summary
DNA double-stranded breaks (DSBs) constitute the most deleterious threat to genomic integrity, and the repair of DNA is essential for normal cell growth and animal development [1]. Resulting differences between such repair in normal and tumor cells can make tumor cells vulnerable to targeted therapies. One such successful paradigm is the induction of synthetic lethality in homologous recombination–deficient (HR-deficient) tumors, which is achieved by treating the tumors with poly(ADP-ribose)polymerase inhibitors (PARPi) [3]. Striatin-interacting phosphatase and kinase (STRIPAK) complexes are supramolecular complexes conserved between various organisms. The centers of these complexes are formed each by the trimeric serine-threonine holoenzyme PP2A, which consists of scaffold subunit A (PP2AA), the catalytic subunit C (PP2AC), and striatin regulatory subunits (STRN1/3/4) [5, 6]. Formation of an intact STRIPAK complex may not require all of these factors, but various combinations of these factors assemble to form different complexes that participate in diverse physiological functions such as tissue development and cellular homeostasis [8, 9]
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