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hDNA 2 nuclease/helicase promotes centromeric DNA replication and genome stability
Author(s) -
Li Zhengke,
Liu Bochao,
Jin Weiwei,
Wu Xiwei,
Zhou Mian,
Liu Vincent Zewen,
Goel Ajay,
Shen Zhiyuan,
Zheng Li,
Shen Binghui
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201796729
Subject(s) - biology , nuclease , helicase , dna replication , dna , genetics , genome , dna binding protein , microbiology and biotechnology , gene , rna , transcription factor
DNA 2 is a nuclease/helicase that is involved in Okazaki fragment maturation, replication fork processing, and end resection of DNA double‐strand breaks. Similar such helicase activity for resolving secondary structures and structure‐specific nuclease activity are needed during DNA replication to process the chromosome‐specific higher order repeat units present in the centromeres of human chromosomes. Here, we show that DNA 2 binds preferentially to centromeric DNA . The nuclease and helicase activities of DNA 2 are both essential for resolution of DNA structural obstacles to facilitate DNA replication fork movement. Loss of DNA 2‐mediated clean‐up mechanisms impairs centromeric DNA replication and CENP ‐A deposition, leading to activation of the ATR DNA damage checkpoints at centromeric DNA regions and late‐S/G2 cell cycle arrest. Cells that escape arrest show impaired metaphase plate formation and abnormal chromosomal segregation. Furthermore, the DNA 2 inhibitor C5 mimics DNA 2 knockout and synergistically kills cancer cells when combined with an ATR inhibitor. These findings provide mechanistic insights into how DNA 2 supports replication of centromeric DNA and give further insights into new therapeutic strategies.