Dealing with DNA damage during mitosis – Biologisk Institut - Københavns Universitet

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Dealing with DNA damage during mitosis

Speaker: Marcel A.T.M. van Vugt, PhD, Department of Medical Oncology, University of Groningen, NL
Host: Professor Michael Lisby, Functional Genomics, BIO-UCPH

Abstract
Cells are equipped with a cell-intrinsic signaling network called the DNA damage response (DDR). This signaling network recognizes DNA lesions and initiates various downstream pathways to coordinate a cell cycle arrest with the repair of the damaged DNA. Alternatively, the DDR can mediate clearance of affected cells that are beyond repair through apoptosis or senescence. The DDR can be activated in response to DNA damage throughout the cell cycle, although the extent of DDR signaling is different in each cell cycle phase. In contrast to interphase cells, only a very marginal response to DNA double strand breaks is observed during mitosis. Different mechanisms appear to be at play to inactivate specific signaling axes of the DDR network in mitosis. We study at the cellular and molecular levels, how DDR signaling is reqired during mitosis, as well as the consequences of encountering DNA damage during mitosis for cellular fate.

Previously, we have identified that Rif1 is in the resolution of DNA catenanes that are visible as ultrafine DNA bridges (UFBs) in anaphase to which PICH and BLM localize. Rif1, which during interphase functions downstream of 53BP1 in DNA repair, is recruited to UFBs in a PICH-dependent fashion, but independently of 53BP1 or BLM. Similar to PICH and BLM, Rif1 promotes the resolution of UFBs: its depletion increases the frequency of nucleoplasmic bridges and RPA70-positive UFBs in late anaphase. Moreover, in the absence of Rif1, PICH, or BLM, more nuclear bodies with damaged DNA arise in ensuing G1 cells, when chromosome decatenation is impaired. Our data revealed a thus far unrecognized function for Rif1 in the resolution of UFBs during anaphase to protect genomic integrity.

More recently, we investigated the role of mitotic progression in the response to anti-neoplastic drugs. HR-deficient cancers are hypersensitive to Poly (ADP ribose)-polymerase (PARP) inhibitors, but can acquire resistance and relapse. Mechanistic understanding how PARP inhibition induces cytotoxicity in HR-deficient cancer cells is incomplete. We found PARP inhibition to compromise replication fork stability in HR-deficient cancer cells, leading to mitotic DNA damage and consequent chromatin bridges and lagging chromosomes in anaphase, frequently leading to cytokinesis failure, multinucleation and cell death. PARP-inhibitor-induced multinucleated cells fail clonogenic outgrowth, and high percentages of multinucleated cells are found in vivo in remnants of PARP inhibitor-treated Brca2/; p53/ and Brca1/;p53/ mammary mouse tumours, suggesting that mitotic progression promotes PARP-inhibitor-induced cell death. Indeed, forced mitotic bypass through EMI1 depletion abrogates PARP-inhibitor-induced cytotoxicity. These findings provide insight into the cytotoxic effects of PARP inhibition, and point at combination therapies to potentiate PARP inhibitor treatment of HR-deficient tumours.