SLX4–XPF mediates DNA damage responses to replication stress induced by DNA–protein interactions

Riko Ishimoto, Yota Tsuzuki, Tomoki Matsumura, Seiichiro Kurashige, Kouki Enokitani, Koki Narimatsu, Mitsunori Higa, Nozomi Sugimoto, Kazumasa Yoshida, Masatoshi Fujita

Research output: Contribution to journalArticlepeer-review

Abstract

The DNA damage response (DDR) has a critical role in the maintenance of genomic integrity during chromosome replication. However, responses to replication stress evoked by tight DNA–protein complexes have not been fully elucidated. Here, we used bacterial LacI protein binding to lacO arrays to make site-specific replication fork barriers on the human chromosome. These barriers induced the accumulation of single-stranded DNA (ssDNA) and various DDR proteins at the lacO site. SLX4–XPF functioned as an upstream factor for the accumulation of DDR proteins, and consequently, ATR and FANCD2 were interdependently recruited. Moreover, LacI binding in S phase caused underreplication and abnormal mitotic segregation of the lacO arrays. Finally, we show that the SLX4–ATR axis represses the anaphase abnormality induced by LacI binding. Our results outline a long-term process by which human cells manage nucleoprotein obstacles ahead of the replication fork to prevent chromosomal instability.

Original languageEnglish
Article numbere202003148
JournalJournal of Cell Biology
Volume220
Issue number1
DOIs
Publication statusPublished - 2021

All Science Journal Classification (ASJC) codes

  • Cell Biology

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