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. Author manuscript; available in PMC: 2023 Nov 1.
Published in final edited form as: Kidney Int. 2022 Aug 2;102(5):1042–1056. doi: 10.1016/j.kint.2022.07.003

Figure 8. Inhibiting cell cycle activity or p21 expression blocks DNA re-replication in FAN1 KO hPTECs.

Figure 8.

(A) Schematics of roscovitine and UC2288 treatment in FAN1 KO hPTEC cells.

(B) Representative Western blot images of DNA replication licensing proteins and DNA damage markers in control, cisplatin treated and cisplatin + roscovitine treated parental and FAN1 KO hPTECs. Proteins were detected either in chromatin extractions or total cell lysates, as indicated. Histone H3 was used as a loading control for chromatin and GAPDH for whole cell lysate.

(C) Representative Western blot images of DNA replication licensing proteins and DNA damage markers in cisplatin treated and cisplatin + UC2288 treated parental and FAN1 KO hPTECs. Proteins were detected either in chromatin extractions or total cell lysates, as indicated. Histone H3 was used as a loading control for chromatin and GAPDH for whole cell lysate.

(D) Model of DNA damage induced cell cycle abnormalities in a DNA repair deficient proximal tubular cell. Kidney proximal tubule cells with proficient DNA repair will resolve non-lethal DNA damage and regenerate the injured tubule. In contrast, DNA repair deficient cells will accumulate DNA damage through replication stress, which leads to abnormal cell cycle activity and p21-dependent stabilization of CDT1 and CDC6. p21 expressing tubular cells undergo DNA re-replication, which propagates further genomic instability and progression to CKD.