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LRRC59 cooperates with nuclear transporters to restrain the nuclear envelope repair machinery and safeguard genome integrity

ABSTRACT: Nuclear envelope (NE) ruptures in primary nuclei and micronuclei are a hallmark of cancer and persistent ruptures drive cancer-associated genome instability and inflammatory signaling. NE repair relies on the activation of the ESCRT-III machinery by the LEMD2-CHMP7 compartmentalization sensor, but very little is known about the repair processes beyond these core factors. In this study, we used convergent proximity proteomics centered on the LEMD2-CHMP7 node to generate the first NE rupture proteomics inventory. Within this NE repairome, we identified LRRC59 as a critical regulator of LEMD2 and CHMP7 accumulation at sites of NE ruptures. We found that assembly of LEMD2-CHMP7 complexes is controlled by LRRC59 and the importin KPNB1, in synergy with the exportin XPO1. Disruption of this novel regulatory axis escalated spreading of LEMD2 and CHMP7 across the NE, driving the accumulation of DNA torsional stress and DNA damage in ruptured primary nuclei and micronuclei. Taken together, our work provides a molecular inventory for studying nuclear integrity and identifies a novel layer of regulation of NE repair centered on LRRC59. We propose that dysregulation of LRRC59 and altered nuclear import/export in cancer cells coordinately perturbs NE repair, driving genome instability and cancer development.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Tuula Nyman

LAB HEAD: Tuula Nyman

PROVIDER: PXD058192 | Pride | 2025-12-12

REPOSITORIES: Pride

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A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements

Project description:Chromosomal instability (CIN) generates micronuclei, aberrant extranuclear structures that catalyze the acquisition of complex chromosomal rearrangements present in cancer. Micronuclei are characterized by persistent DNA damage and catastrophic nuclear envelope collapse, exposing DNA to the cytoplasm and driving a pro-inflammatory, pro-metastatic environment. Here, we identify the autophagic receptor p62/SQSTM1 as a regulator of micronuclei. p62 modulates micronuclear stability, influencing chromosome fragmentation and rearrangements, via exerting local spatial control on peri-micronuclear ESCRT-mediated repair activity. We demonstrate that proximity of micronuclei to mitochondria leads to oxidation-driven homo-oligomerization of p62, which triggers autophagic degradation of ESCRT components, thereby limiting their repair activity. Notably, we find that p62 levels correlate with increased chromothripsis across human cancer cell lines and with increased CIN in colorectal tumors. Thus, our study identifies p62 as a novel regulator of micronuclei and indicates that it may serve as a prognostic marker of tumors with high CIN.

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Replication Stress Causes Mitotic Nuclear Envelope Reassembly Defect

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Project description:The integrity of the nuclear envelope (NE) is essential to maintain the structural stability of the nucleus. Rupture of the NE has been frequently observed in cancer cells, especially in the context of mechanical challenges, such as physical confinement and migration. However, spontaneous NE rupture events have also been described, without any obvious physical challenges to the cell. The molecular mechanism(s) of these spontaneous NE rupture events remain to be explored. Here, we show that DNA damage and subsequent ATR activation can lead to NE rupture. Upon DNA damage, Lamin A/C is phosphorylated in an ATR-dependent manner, leading to changes in lamina assembly and, ultimately, NE rupture. In addition, we show that cancer cells with intrinsic DNA repair defects undergo frequent events of DNA damage-induced NE rupture, which renders them extremely sensitive to further NE perturbations. Exploiting this NE vulnerability could provide a new angle to complement traditional, DNA damage-based chemotherapy.

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DNA damage induces nuclear envelope rupture through ATR-mediated phosphorylation of Lamin A/C - Synthetic Peptide

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Retinoic acid-induced 2 protein contributes to proficient homologous recombination and maintains genomic stability in breast cancer

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