The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis

Abstract

The accurate repair of DNA double-strand breaks (DSBs), highly toxic DNA lesions, is crucial for genome integrity and is tightly regulated during the cell cycle. In mitosis, cells inactivate DSB repair in favor of a tethering mechanism that stabilizes broken chromosomes until they are repaired in the subsequent cell cycle phases. How this is achieved mechanistically is not yet understood, but the adaptor protein TOPBP1 is critically implicated in this process. Here, we identify CIP2A as a TOPBP1-interacting protein that regulates TOPBP1 localization specifically in mitosis. Cells lacking CIP2A display increased micronuclei formation, DSB repair defects and chromosomal instability. CIP2A is actively exported from the cell nucleus in interphase but, upon nuclear envelope breakdown at the onset of mitosis, gains access to chromatin where it forms a complex with MDC1 and TOPBP1 to promote TOPBP1 recruitment to sites of mitotic DSBs. Collectively, our data uncover CIP2A-TOPBP1 as a mitosis-specific genome maintenance complex.

Phosphorylation-dependent assembly of DNA damage response systems and the central roles of TOPBP1

“…CIP2A appears to primarily interact with a region of TOPBP1 between BRCT5 and BRCT6, but whether its interaction is dependent on phosphorylation is unclear. The two studies make different conclusions about the function of CIP2A in TOPBP1 biology, with one [69] showing a particular involvement in the repair of DNA double-strand breaks occurring during mitosis, while the other [70] suggesting a more general role in dampening DNA damage checkpoint signalling. In any event, CIP2A appears to be an essential factor for the roles of TOPBP1 in maintaining genomic stability, but more work will be required to understand the biochemical mechanism by which this is accomplished.…”

“…Although not an enzyme itself, but rather a regulator of one - the protein phosphatase PP2A inhibitor CIP2A has recently been characterised as an essential TOPBP1 interactor [69] , [70] . CIP2A appears to primarily interact with a region of TOPBP1 between BRCT5 and BRCT6, but whether its interaction is dependent on phosphorylation is unclear.…”

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].…”

Biology before the SOS Response—DNA Damage Mechanisms at Chromosome Fragile Sites

“…A hint that humans might have a similar mechanism(s) is suggested by the recent finding that human topoisomerase, TOP3A, is implicated in the promotion of DSB formation and the resolution of chromosome bridges at CFSs [60]. Moreover, a topoisomerase-interacting protein, TOPBP1, is associated with improved stability at fragile sites [61,62], suggesting to us that topoisomerase half reactions might underly the fragility of CFS. TOPBP1 binds and might modulate the activity or fidelity of the TOP2A type II-topoisomerase, which decatenates human sister chromosomes.…”