Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors.

Oncogene-induced replication stress, for instance as a result of Cyclin E1 overexpression, causes genomic instability and has been linked to tumorigenesis. To survive high levels of replication stress, tumors depend on pathways to deal with these DNA lesions, which represent a therapeutically actionable vulnerability. We aimed to uncover the consequences of Cyclin E1 or Cdc25A overexpression on replication kinetics, mitotic progression, and the sensitivity to inhibitors of the WEE1 and ATR replication checkpoint kinases.

Premature mitotic entry induced by ATR inhibition potentiates olaparib inhibition-mediated genomic instability, inflammatory signaling, and cytotoxicity in BRCA2-deficient cancer cells.

Poly(ADP-ribose) polymerase (PARP) inhibitors are selectively cytotoxic in cancer cells with defects in homologous recombination (HR) (e.g., due to BRCA1/2 mutations).

Replication stress: Driver and therapeutic target in genomically instable cancers.

Genomically instable cancers are characterized by progressive loss and gain of chromosomal fragments, and the acquisition of complex genomic rearrangements. Such cancers, including triple-negative breast cancers and high-grade serous ovarian cancers, typically show aggressive behavior and lack actionable driver oncogenes. Increasingly, oncogene-induced replication stress or defective replication fork maintenance is considered an important driver of genomic instability.

Never tear us a-PARP: Dealing with DNA lesions during mitosis.

Tumors defective in homologous recombination (HR) are highly sensitive to poly ADP-ribose polymerase (PARP) inhibition, however the cell biological mechanisms underlying this synthetic lethality remain elusive. We recently identified that PARP inhibitor-induced DNA lesions persist until mitosis, subsequently causing mitotic chromatin bridges, multinucleation and apoptosis. Here, we discuss the implications of these findings.

Progression through mitosis promotes PARP inhibitor-induced cytotoxicity in homologous recombination-deficient cancer cells.

Mutations in homologous recombination (HR) genes BRCA1 and BRCA2 predispose to tumorigenesis. 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.

Rif1 Is Required for Resolution of Ultrafine DNA Bridges in Anaphase to Ensure Genomic Stability.

Sister-chromatid disjunction in anaphase requires the resolution of DNA catenanes by topoisomerase II together with Plk1-interacting checkpoint helicase (PICH) and Bloom's helicase (BLM). We here identify Rif1 as a factor involved 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.

p73 engages A2B receptor signalling to prime cancer cells to chemotherapy-induced death.

Tumour cells often acquire the ability to escape cell death, a key event leading to the development of cancer. In almost half of all human cancers, the capability to induce cell death is reduced by the mutation and inactivation of p53, a tumour suppressor protein that is a central regulator of apoptosis. As a result, there is a crucial need to identify different cell death pathways that could be targeted in malignancies lacking p53.

ATR inhibition preferentially targets homologous recombination-deficient tumor cells.

Homologous recombination (HR) is required for faithful repair of double-strand DNA breaks. Defects in HR repair cause severe genomic instability and challenge cellular viability. Paradoxically, various cancers are HR defective and have apparently acquired characteristics to survive genomic instability.