Mitotic DNA damage promotes chromokinesin- mediated missegregation of polar chromosomes in cancer cells

• Type: Article in International Scientific Journal
• Date: 2023

Authors

Novais Cruz, M (Author) Other; Pombinho, A (Author) Other; Sousa, M (Author) Other; Maia, AF (Author) Other; Helder Maiato (Author) FMUP; Ferras, C (Author) Other

Journal

Title: Molecular Biology of the Cell

Vol. 34

Pages: 4-19

ISSN: 1059-1524

Publisher: American Society for Cell Biology

Indexing

ISI Web of Knowledge - 0 Citations

Scopus - 0 Citations

Other information

Authenticus ID: P-00Y-7V3

DOI: 10.1091/mbc.e22-11-0518

Abstract (EN): DNA damage response (DDR) during interphase involves active signaling and repair to ensure genomic stability. However, how mitotic cells respond to DNA damage re-mains poorly understood. Supported by correlative live-/fixed-cell microscopy, it was found that mitotic cells exposed to several cancer chemotherapy compounds acquire and signal DNA damage, regardless of how they interact with DNA. In-depth analysis upon DNA dam-age during mitosis revealed a spindle assembly checkpoint (SAC)-dependent, but ataxia telangiectasia mutated-independent, mitotic delay. This delay was due to the presence of mis-aligned chromosomes that ultimately satisfy the SAC and missegregate, leading to micronuclei formation. Mechanistically, it is shown that mitotic DNA damage causes missegregation of polar chromosomes due to the action of arm-ejection forces by chromokinesins. Importantly, with the exception of DNA damage induced by etoposide-a topoisomerase II inhibitor-this outcome was independent of a general effect on kinetochore microtubule stability. Colony formation assays in pan-cancer cell line models revealed that mitotic DNA damage causes distinct cytotoxic effects, depending on the nature and extent of the damage. Overall, these findings unveil and raise awareness that therapeutic DNA damage regimens may contribute to genomic instability through a surprising link with chromokinesin-mediated missegregation of polar chromosomes in cancer cells.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 16