hDNA2 nuclease/helicase promotes centromeric DNA replication and genome stability.

The EMBO Journal
Zhengke LiBinghui Shen

Abstract

DNA2 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 DNA2 binds preferentially to centromeric DNA The nuclease and helicase activities of DNA2 are both essential for resolution of DNA structural obstacles to facilitate DNA replication fork movement. Loss of DNA2-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 DNA2 inhibitor C5 mimics DNA2 knockout and synergistically kills cancer cells when combined with an ATR inhibitor. These findings provide mechanistic insights into how DNA2 supports replication of centromeric DNA and give further insights into new therapeutic strategies.

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Citations

Sep 25, 2019·Plants·Stewart A MorleyBrent L Nielsen
Sep 4, 2019·Annals of Clinical and Translational Neurology·Dario RonchiGiacomo Pietro Comi
Jul 16, 2019·DNA Repair·Yijie WangYingfei Wang
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May 21, 2021·Nature Communications·Yijie WangYingfei Wang
Jan 29, 2020·Journal of the American Chemical Society·Jan JamroskovicNasim Sabouri

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Datasets Mentioned

BETA
GSE108619

Methods Mentioned

BETA
immunoprecipitation
pull down
ChIP
flow cytometry
fluorescence
X‐ray
fluorescence microscopy
transfection
PCR
scraping

Software Mentioned

Novoalign
chipseq ”
UCSC genome browser
RSAT
RepeatMasker
custom R scripts
Bioconductor package “
RNAfold
Summit

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