Human Endonuclease ANKLE1 Localizes at the Midbody and Processes Chromatin Bridges to Prevent DNA Damage and cGAS‐STING Activation

Abstract

Chromatin bridges connecting the two segregating daughter nuclei arise from chromosome fusion or unresolved interchromosomal linkage. Persistent chromatin bridges are trapped in the cleavage plane, triggering cytokinesis delay. The trapped bridges occasionally break during cytokinesis, inducing DNA damage and chromosomal rearrangements. Recently, Caenorhabditis elegans LEM‐3 and human TREX1 nucleases have been shown to process chromatin bridges. Here, it is shown that ANKLE1 endonuclease, the human ortholog of LEM‐3, accumulates at the bulge‐like structure of the midbody via its N‐terminal ankyrin repeats. Importantly, ANKLE1−/− knockout cells display an elevated level of G1‐specific 53BP1 nuclear bodies, prolonged activation of the DNA damage response, and replication stress. Increased DNA damage observed in ANKLE1−/− cells is rescued by inhibiting actin polymerization or reducing actomyosin contractility. ANKLE1 does not act in conjunction with structure‐selective endonucleases, GEN1 and MUS81 in resolving recombination intermediates. Instead, ANKLE1 acts on chromatin bridges by priming TREX1 nucleolytic activity and cleaving bridge DNA to prevent the formation of micronuclei and cytosolic dsDNA that activate the cGAS‐STING pathway. It is therefore proposed that ANKLE1 prevents DNA damage and autoimmunity by cleaving chromatin bridges to avoid catastrophic breakage mediated by actomyosin contractile forces.

A benzochalcone derivative synchronously induces apoptosis and ferroptosis in pancreatic cancer cells

“…4B ). These genes have diverse functions and their dysregulation in cancer cells may contribute to tumor development, progression, and response to treatment ( Salomaa et al., 2021 ; Li et al., 2018 ; Shi et al., 2019 ; Jiang et al., 2023 ). Interestingly, TCGA and GTEx data demonstrated higher expression levels of PLAC8, NME1-NME2, and TMEM14A in pancreatic cancer patients as illustrated in Fig.…”

The Calpain-7 protease functions together with the ESCRT-III protein IST1 within the midbody to regulate the timing and completion of abscission

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Pauperization of Emerin from nuclear envelope during chromatin bridge resolution drives prostate cancer cell migration and invasiveness

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