Journal
GENES & DEVELOPMENT
Volume 34, Issue 15-16, Pages 1065-1074Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.330050.119
Keywords
RTEL1; helicase; R-loop; DNA:RNA hybrid; Poldip3; POL delta; polymerase delta; DNA repair; DNA damage response; telomere maintenance; dyskeratosis congenita; Hoyeral-Hreiderson syndrome
Categories
Funding
- Karolinska Institutet
- Alfred Benzon's Foundation
- Swedish Cancer Society [170176]
- Swedish Research Council [VR-MH 2014-46602-117891-30]
- Strategic Research Program in Cancer at Karolinska Institutet [2201]
- Novo Nordisk Foundation [16854]
- Danish Cancer Society [R1123-A7785-15-S2]
- Danish Council for Independent Research [DFF-7016-00313]
- Danish National Research Foundation [DNRF125]
- Lundbeck Foundation [R266-2017-4289]
- Agence Nationale de la Recherche NR [ANR-14-CE10-0006]
- Fondation ARC pour la Recherche contre le Cancer
- Agence Nationale de la Recherche (ANR) [ANR-14-CE10-0006] Funding Source: Agence Nationale de la Recherche (ANR)
Ask authors/readers for more resources
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 comple-mentary human cell culture models established that RTEL1 and the Pol delta 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 sup-pression at genomic regions where transcription and replication intersect, with implications for human diseases including cancer.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available