CIP2A is a prime synthetic-lethal target for BRCA-mutated cancers

Abstract

BRCA1/2-mutated cancer cells must adapt to the genome instability caused by their deficiency in homologous recombination. Identifying and targeting these adaptive mechanisms may provide new therapeutic strategies. Here we present the results of genome-scale CRISPR/Cas9-based synthetic lethality screens in isogenic pairs of BRCA1- and BRCA2-deficient cells that identified the gene encoding CIP2A as essential in a wide range of BRCA1- and BRCA2-mutated cells. Unlike PARP inhibition, CIP2A-deficiency does not cause accumulation of replication-associated DNA lesions that require homologous recombination for their repair. CIP2A is cytoplasmic in interphase but, in mitosis, accumulates at DNA lesions as part of a complex with TOPBP1, a multifunctional genome stability factor. In BRCA-deficient cells, the CIP2A-TOPBP1 complex prevents lethal mis-segregation of acentric chromosomes that arises from impaired DNA synthesis. Finally, physical disruption of the CIP2A-TOPBP1 complex is highly deleterious in BRCA-deficient cells and tumors, indicating that targeting this mitotic chromosome stability process represents an attractive synthetic-lethal therapeutic strategy for BRCA1- and BRCA2-mutated cancers.

Sister chromatid exchanges induced by perturbed replication are formed independently of homologous recombination factors

“…In this context, a requirement for mitotic replisome unloading by TRAIP/p97, fits well with observed sensitization of HR-deficient cells for PARP inhibition upon inactivation of TRAIP (Fugger et al, 2021), and the observation that progression through mitosis promotes PARP inhibitor-mediated cell death (Schoonen et al, 2017). Our observation that PARP inhibitor-induced DNA lesions in HR-deficient cells are transmitted into mitosis also aligns well the recent identification of the DNA tethering factor CIP2A being essential in HR-deficient cells (Adam et al, 2021), and was identified in our proteomics analysis of mitotic factors that bind DNA ends. Further research is warranted to investigate whether tethering of DNA ends is required to ligate DNA ends upon cleavage of stalled replication forks during mitosis.…”

“…Mass spectrometry analysis revealed a range of proteins that was enriched on synthetic DNA breaks in mitotic extracts, including Cip2a and Topbp1 (Fig. 4F), which together with Mdc1 are involved in mitotic tethering of mitotic DNA breaks (Adam et al, 2021; Leimbacher et al, 2019). Intriguingly, we also identified the single-strand annealing (SSA) factor Rad52 and the alternative end-joining (alt-EJ) factor Polq (Fig.…”

Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency

“…In particular, the central recombination protein RAD51 functions in replication gap suppression (RGS) in a manner that is separated for its role in HR or post-replication gap filling (Kolinjivadi et al, 2017b;Su et al, 2008). Replication gaps could be the basis for underreplication in BRCA-deficient cells that provides opportunities for synthetic lethal interactions, with loss of genes functioning during or in the resolution of replication (Adam et al, 2021;A ´lvarez-Quilo ´n et al, 2020;Feng and Jasin, 2017;Lai et al, 2017) We also noted that DSB framework requires concessions because HR and FP vary in their relation to PARPi response in several cell models (Cantor and Calvo, 2017;Kolinjivadi et al, 2017b;Mijic et al, 2017;Schlacher et al, 2011;Wang et al, 2015;Zadorozhny et al, 2017). Here, we considered that immediate induction of widespread replication gaps could drive syn-thetic lethality.…”

When breaks get hot: inflammatory signaling in BRCA1/2-mutant cancers

“…POLQ inhibition yields micronuclei and IFN signaling [95], illustrating that utilization of alternative repair pathways in BRCA1/2 mutant cancers prevents excessive missegregation of chromosome fragments and the accumulation of cytoplasmic DNA. Likewise, BRCA1/2-mutant cells depend on Cip2A and TopBp1, which form a complex with Mdc1 to tether chromosome fragments during mitosis, preventing the generation of micronuclei [96,97]. In addition, several mechanisms have been described by which HR-deficient cells can manage with defective replication fork protection, including the inactivation of PAXIP1 [98] and EZH2 [99].…”