hDNA2 nuclease/helicase promotes centromeric DNA replication and genome stability
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 pro...
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Published in | The EMBO journal Vol. 37; no. 14 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Blackwell Publishing Ltd
13.07.2018
John Wiley and Sons Inc |
Subjects | |
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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.
Synopsis
Whole genome screening uncovers an essential role of DNA2 helicase/nuclease, known to be involved in replication fork processing and double‐strand break resection, in resolution of DNA secondary structures arising during replication of centromeric repeat DNA.
Human DNA2 is specifically recruited to centromeric DNA regions of the genome.
The nuclease and helicase activities of DNA2 are both essential for resolution of DNA structural obstacles to facilitate replication fork movement.
Loss of DNA2‐mediated clean‐up mechanisms impairs centromeric replication and causes defects in CENP‐A deposition, leading to ATR checkpoint activation and late‐S/G2 cell cycle arrest.
Combined application of the DNA2 and ATR inhibitors synergistically kills cancer cells and may offer new therapeutic strategies.
Whole genome screening uncovers an essential role of DNA2 helicase/nuclease in resolution of DNA secondary structures to facilitate replication of centromeric repeat DNA. |
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AbstractList | 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. 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. Synopsis Whole genome screening uncovers an essential role of DNA2 helicase/nuclease, known to be involved in replication fork processing and double‐strand break resection, in resolution of DNA secondary structures arising during replication of centromeric repeat DNA. Human DNA2 is specifically recruited to centromeric DNA regions of the genome. The nuclease and helicase activities of DNA2 are both essential for resolution of DNA structural obstacles to facilitate replication fork movement. Loss of DNA2‐mediated clean‐up mechanisms impairs centromeric replication and causes defects in CENP‐A deposition, leading to ATR checkpoint activation and late‐S/G2 cell cycle arrest. Combined application of the DNA2 and ATR inhibitors synergistically kills cancer cells and may offer new therapeutic strategies. Whole genome screening uncovers an essential role of DNA2 helicase/nuclease in resolution of DNA secondary structures to facilitate replication of centromeric repeat DNA. 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. |
Author | Li, Zhengke Zheng, Li Shen, Zhiyuan Shen, Binghui Zhou, Mian Jin, Weiwei Liu, Vincent Zewen Wu, Xiwei Liu, Bochao Goel, Ajay |
AuthorAffiliation | 1 Department of Cancer Genetics and Epigenetics Beckman Research Institute City of Hope Duarte CA USA 2 Department of Radiation Oncology Rutgers Cancer Institute of New Jersey Rutgers Robert Wood Johnson Medical School Rutgers, the State University of New Jersey New Brunswick NJ USA 5 Department of Computer Science Columbia University New York NY USA 4 Department of Molecular and Cellular Biology Beckman Research Institute City of Hope Duarte CA USA 6 Center for Gastrointestinal Research Center for Translational Genomics and Oncology Baylor Scott and White Research Institute and Charles A. Sammons Cancer Center Baylor University Medical Center Dallas TX USA 3 Department of Gastroenterology & Pancreatic Surgery Zhejiang Provincial People's Hospital Hangzhou Zhejiang China |
AuthorAffiliation_xml | – name: 5 Department of Computer Science Columbia University New York NY USA – name: 2 Department of Radiation Oncology Rutgers Cancer Institute of New Jersey Rutgers Robert Wood Johnson Medical School Rutgers, the State University of New Jersey New Brunswick NJ USA – name: 3 Department of Gastroenterology & Pancreatic Surgery Zhejiang Provincial People's Hospital Hangzhou Zhejiang China – name: 6 Center for Gastrointestinal Research Center for Translational Genomics and Oncology Baylor Scott and White Research Institute and Charles A. Sammons Cancer Center Baylor University Medical Center Dallas TX USA – name: 4 Department of Molecular and Cellular Biology Beckman Research Institute City of Hope Duarte CA USA – name: 1 Department of Cancer Genetics and Epigenetics Beckman Research Institute City of Hope Duarte CA USA |
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Keywords | centromere DNA2 chromosome segregation cell cycle arrest centromeric DNA replication |
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Snippet | DNA2 is a nuclease/helicase that is involved in Okazaki fragment maturation, replication fork processing, and end resection of DNA double‐strand breaks.... DNA2 is a nuclease/helicase that is involved in Okazaki fragment maturation, replication fork processing, and end resection of DNA double-strand breaks.... DNA 2 is a nuclease/helicase that is involved in Okazaki fragment maturation, replication fork processing, and end resection of DNA double‐strand breaks.... |
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SubjectTerms | Activation Cancer Cell Cycle cell cycle arrest Cell Line centromere Centromere - metabolism Centromeres centromeric DNA replication chromosome segregation Chromosomes Chromosomes, Human - metabolism Deoxyribonucleic acid Deposition DNA DNA biosynthesis DNA damage DNA helicase DNA Helicases - deficiency DNA Helicases - metabolism DNA Replication DNA2 Eukaryotes Genomes Genomic Instability Humans Inhibitors Metaphase Nuclease Plates (structural members) Replication |
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Title | hDNA2 nuclease/helicase promotes centromeric DNA replication and genome stability |
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