Preprint Hypothesis Version 1 Preserved in Portico This version is not peer-reviewed

Repair and misrepair of telomeric DNA in dynamic interactions with PML nuclear bodies and lamin B1. A gear-wheel nuclear traffic.

Version 1 : Received: 29 December 2023 / Approved: 3 January 2024 / Online: 3 January 2024 (05:45:38 CET)
Version 2 : Received: 4 January 2024 / Approved: 5 January 2024 / Online: 5 January 2024 (10:06:39 CET)

How to cite: Salmina, K.; Rūmnieks, F.; Pjanova, D.; Erenpreisa, J. Repair and misrepair of telomeric DNA in dynamic interactions with PML nuclear bodies and lamin B1. A gear-wheel nuclear traffic.. Preprints 2024, 2024010111. https://doi.org/10.20944/preprints202401.0111.v1 Salmina, K.; Rūmnieks, F.; Pjanova, D.; Erenpreisa, J. Repair and misrepair of telomeric DNA in dynamic interactions with PML nuclear bodies and lamin B1. A gear-wheel nuclear traffic.. Preprints 2024, 2024010111. https://doi.org/10.20944/preprints202401.0111.v1

Abstract

Telomeres in epithelial tumours are usually maintained by telomerase, however, in the breast cancer MDA-MB-231 cell line, polyploid cells, induced by doxorubicin (DOX) were found, after mitotic slippage, transiently shifting to recombinatory alternative telomere lengthening (ALT) in PML bodies (APBs). The involvement of the meiotic recombination proteins was evidenced here by juxta-co-localisation of SPO11, DMC1 and RAD51/γH2AX with APBs in these and melanoma SkMel28-DOX-treated cells. Using sublethal doses of DOX we also observed the formation of the PML dimeric rod tandems linking γH2AX/TRF2 foci into ribbons discontinuously inserted into lamin B1 and circumventing cell nuclei. Next, we link these PML-lamin B1 insertions and peripheral rotation of the tandemly linked telomere repeats with the mobility of the nuclear envelope limited chromatin sheets (ELCS). ELCSs comprise two layers of the criss-crossed ~30 nm granules derived from surface heterochromatin (epichromatin) which contains telomere repeats enriched in GpC, PML, and ALU. ELCS protrude, circumvent, loop, split, fuse, and rejoin polyploid cell nuclei. We propose this gear-wheel-like turnover of telomere repeats to be used for the homology search. Interstitial and end-telomere repeats flanked by fragile ALU-Z flipons become recognised by SPO11 nuclease, attract TRF2, PML, and meiotic recombinases. Subsequently, they perform ALT recombining subtelomeres and telomeres or undergo non-homologous end-joining and chromosome rearrangements with ELCS. This mechanism increases the chance of cell survival and may be involved in chromothripsis.

Keywords

Cancer; cellular senescence; telomere attrition; alternative telomere lengthening; PML nuclear bodies; lamin B1; ALU; surface heterochromatin; nuclear rotation; chromothripsis

Subject

Biology and Life Sciences, Cell and Developmental Biology

Comments (1)

Comment 1
Received: 3 January 2024
Commenter:
The commenter has declared there is no conflict of interests.
Comment: The authors apologize for the error in Fig.4B: the colour for yH2AX should be designated as green, while PML - red.
Jekaterina Erenpreisa
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