Journal Article

DKFZ-2026-00662

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Cell-cycle-specific lesion evolution rather than inhibition of double-strand-break repair underpins cisplatin radiosensitization.

Qiu, Y. ; Lin, X. ; Mladenov, E. ; Mladenova, V. ; Thomale, J. ; Sak, A. ; Wang, Y. ; Deng, Y. ; Gkika, E. ; Stuschke, M.DKFZ* ; Iliakis, G.

2026
John Wiley & Sons, Inc. Hoboken, NJ

Abstract: DNA double-strand breaks (DSBs) generated from collisions of DNA replication forks with cisplatin-induced interstrand crosslinks underpin cisplatin cytotoxicity. Yet, the impact of cell-cycle-dependent cisplatin-DNA adduct (CDA) formation on cell cycle progression and interactions with DNA replication remain incompletely characterized. Also, although cisplatin enhances tumor response to ionizing radiation (IR), the underpinning radiosensitizing mechanisms remain unresolved. Here, we close this void and analyze CDAs (GpG crosslinks) and DSB (γH2AX foci) induction and repair in a strictly cell-cycle-dependent manner. We report for the first time that CDAs form in a dose- and time-dependent manner in all cell cycle phases, whereas DSBs emerge only in S-phase. Repair of IR-induced DSBs remains largely unaffected by CDAs in G1, S, and G2 phases, but is inhibited when S-phase-treated cells progressed to G2. Radiosensitization occurs after prolonged cisplatin exposure, likely owing to G2-phase accumulation and lesion evolution from S-phase, thus impairing repair of IR-induced DSBs. Cisplatin fails to radiosensitize quiescent (G0) cells. In summary, CDA formation is similar across the cell cycle, but DSBs form only in S-phase. Whereas CDAs fail to interfere with repair of IR-induced DSBs, progression-dependent repair disruptions cause radiosensitization. Elucidation of the underpinning mechanisms may help to design improved cisplatin-radiation schedules for more efficacious therapies.

Keyword(s): DNA double‐strand breaks ; DNA repair ; cell cycle ; cisplatin ; cisplatin‐DNA adducts ; radiosensitization

Note: #DKTKZFB9# / epub

---

Contributing Institute(s):

1. DKTK Koordinierungsstelle Essen/Düsseldorf (ED01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

---

Database coverage:
; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; DEAL Wiley ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---