Human RTEL1 associates with Poldip3 to facilitate responses to replication stress and R-loop resolution
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Human RTEL1 associates with Poldip3 to facilitate responses to replication stress and R-loop resolution. / Björkman, Andrea; Johansen, Søren L.; Lin, Lin; Schertzer, Mike; Kanellis, Dimitris C; Katsori, Anna-Maria; Christensen, Søren T.; Luo, Yonglun; Andersen, Jens S.; Elsässer, Simon J.; Londono-Vallejo, Arturo; Bartek, Jiri; Schou, Kenneth B.
I: Genes & Development, Bind 34, Nr. 15-16, 2020, s. 1065-1074.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Human RTEL1 associates with Poldip3 to facilitate responses to replication stress and R-loop resolution
AU - Björkman, Andrea
AU - Johansen, Søren L.
AU - Lin, Lin
AU - Schertzer, Mike
AU - Kanellis, Dimitris C
AU - Katsori, Anna-Maria
AU - Christensen, Søren T.
AU - Luo, Yonglun
AU - Andersen, Jens S.
AU - Elsässer, Simon J.
AU - Londono-Vallejo, Arturo
AU - Bartek, Jiri
AU - Schou, Kenneth B.
N1 - © 2020 Björkman et al.; Published by Cold Spring Harbor Laboratory Press.
PY - 2020
Y1 - 2020
N2 - RTEL1 helicase is a component of DNA repair and telomere maintenance machineries. While RTEL1's role in DNA replication is emerging, how RTEL1 preserves genomic stability during replication remains elusive. Here we used a range of proteomic, biochemical, cell, and molecular biology and gene editing approaches to provide further insights into potential role(s) of RTEL1 in DNA replication and genome integrity maintenance. Our results from complementary human cell culture models established that RTEL1 and the Polδ subunit Poldip3 form a complex and are/function mutually dependent in chromatin binding after replication stress. Loss of RTEL1 and Poldip3 leads to marked R-loop accumulation that is confined to sites of active replication, enhances endogenous replication stress, and fuels ensuing genomic instability. The impact of depleting RTEL1 and Poldip3 is epistatic, consistent with our proposed concept of these two proteins operating in a shared pathway involved in DNA replication control under stress conditions. Overall, our data highlight a previously unsuspected role of RTEL1 and Poldip3 in R-loop suppression at genomic regions where transcription and replication intersect, with implications for human diseases including cancer.
AB - RTEL1 helicase is a component of DNA repair and telomere maintenance machineries. While RTEL1's role in DNA replication is emerging, how RTEL1 preserves genomic stability during replication remains elusive. Here we used a range of proteomic, biochemical, cell, and molecular biology and gene editing approaches to provide further insights into potential role(s) of RTEL1 in DNA replication and genome integrity maintenance. Our results from complementary human cell culture models established that RTEL1 and the Polδ subunit Poldip3 form a complex and are/function mutually dependent in chromatin binding after replication stress. Loss of RTEL1 and Poldip3 leads to marked R-loop accumulation that is confined to sites of active replication, enhances endogenous replication stress, and fuels ensuing genomic instability. The impact of depleting RTEL1 and Poldip3 is epistatic, consistent with our proposed concept of these two proteins operating in a shared pathway involved in DNA replication control under stress conditions. Overall, our data highlight a previously unsuspected role of RTEL1 and Poldip3 in R-loop suppression at genomic regions where transcription and replication intersect, with implications for human diseases including cancer.
U2 - 10.1101/gad.330050.119
DO - 10.1101/gad.330050.119
M3 - Journal article
C2 - 32561545
VL - 34
SP - 1065
EP - 1074
JO - Genes & Development
JF - Genes & Development
SN - 0890-9369
IS - 15-16
ER -
ID: 244240743