Biology subjects

de Boer, H. R.

Publications and source records attributed to de Boer, H. R..

3 recordsLinked to original sources

bioRxiv2026

p53 activity links chromosomal instability to pro-migratory extracellular vesicles

Chromosomal instability (CIN) promotes tumor evolution and metastasis while imposing cellular stress that can limit cell proliferation via activation of p53 and its downstream effector p21. However, how cells recover from this p53-mediated proliferation block while adopting a more malignant fate remains poorly understood. Here, using a p21-RFP reporter in p53-proficient NIH/3T3 cells, we show that acute CIN gives rise to two phenotypically distinct p21 cell populations with divergent recovery trajectories. p21-RFPLOW cells re-enter the cell cycle following a short cell-cycle arrest, while p21-RFPHIGH cells display a more persistent arrest that coincides with a senescence-like state. Longitudinal transcriptomic and extracellular vesicle (EV) proteomic analyses reveal that extracellular-matrix (ECM)- and adhesion-associated programs are initially suppressed following CIN but specifically reactivated in p21-RFPHIGH cells. The content of late-stage p21-RFPHIGH-derived EVs is enriched for ECM-, adhesion-, and cytoskeleton-associated proteins compared with that of p21-RFPLOW-derived EVs. Consequently, EVs derived from p21-RFPHIGH cells confer increased migration. Together, these findings reveal that CIN can yield distinct p21-expressing cell populations that display different cell-cycle recovery trajectories, EV makeup, and migration-associated paracrine activity.

cancer biology↗

bioRxiv2026

CIP2A tetramerization is required for mitotic DNA repair

DNA lesions that persist in mitosis threaten genome stability. These lesions recruit TOPBP1-CIP2A, a complex crucial to tether and process damaged DNA on mitotic chromosomes. Importantly, CIP2A is synthetic lethal in BRCA1/2 mutant cancer cells. However, mechanistic insight into the function of CIP2A is lacking. Here we provide first structural insights into full-length CIP2A and reveal how CIP2A dimers, 46 nm in length, assemble via conserved C-terminal motifs into dumbbell-like tetramers. DNA repair signatures demonstrate that CIP2A tetramerization is crucial for mitotic DNA repair by polymerase theta (POLQ). Tetramerization of CIP2A is needed to recruit POLQ to mitotic DNA lesions and to prevent micronucleation upon replication-born DNA lesions. Tetramerization-defective CIP2A mutants specifically decrease survival of BRCA1/2 mutant cancer cells in a dominant negative manner. Combined, we demonstrate that CIP2A tetramers are crucial components of a mitotic DNA-tethering and repair scaffold, which processes replication-mediated DNA lesions that persist in mitosis.

cell biology↗

bioRxiv2021

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

Sister chromatid exchanges (SCEs) are products of joint DNA molecule resolution, and are considered to form through homologous recombination (HR). Indeed, upon generation of irradiation-induced DNA breaks, SCE induction was compromised in cells deficient for canonical HR factors BRCA1, BRCA2 and RAD51. Contrarily, replication-blocking agents, including PARP inhibitors, induced SCEs independently of BRCA1, BRCA2 and RAD51. PARP inhibitor-induced SCEs were enriched at common fragile sites (CFSs), and were accompanied by post-replicative single-stranded DNA (ssDNA) gaps. Moreover, PARP inhibitor-induced replication lesions were transmitted into mitosis, suggesting that SCEs originate from mitotic processing of under-replicated DNA. We found that DNA polymerase theta (POLQ) was recruited to mitotic DNA lesions, and loss of POLQ resulted in reduced SCE numbers and severe chromosome fragmentation upon PARP inhibition in HR-deficient cells. Combined, our data show that PARP inhibition generates under-replicated DNA, which is transferred into mitosis and processed into SCEs, independently of canonical HR factors.

cancer biology↗