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ATAD5 restricts R-loop formation through PCNA unloading and RNA helicase maintenance at the replication fork

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Title
ATAD5 restricts R-loop formation through PCNA unloading and RNA helicase maintenance at the replication fork
Author(s)
Sangin Kim; Nalae Kang; Su Hyung Park; James Wells; Taejoo Hwang; Eunjin Ryu; Byung-gyu Kim; Sunyoung Hwang; Seong-jung Kim; Sukhyun Kang; Semin Lee; Peter Stirling; Kyungjae Myung; Kyoo-young Lee
Subject
Genome integrity, repair and replication
Publication Date
2020-07
Journal
NUCLEIC ACIDS RESEARCH, v.48, no.13, pp.7218 - 7238
Publisher
OXFORD UNIV PRESS
Abstract
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. R-loops are formed when replicative forks collide with the transcriptional machinery and can cause genomic instability. However, it is unclear how R-loops are regulated at transcription-replication conflict (TRC) sites and how replisome proteins are regulated to prevent R-loop formation or mediate R-loop tolerance. Here, we report that ATAD5, a PCNA unloader, plays dual functions to reduce R-loops both under normal and replication stress conditions. ATAD5 interacts with RNA helicases such as DDX1, DDX5, DDX21 and DHX9 and increases the abundance of these helicases at replication forks to facilitate R-loop resolution. Depletion of ATAD5 or ATAD5-interacting RNA helicases consistently increases R-loops during the S phase and reduces the replication rate, both of which are enhanced by replication stress. In addition to R-loop resolution, ATAD5 prevents the generation of new R-loops behind the replication forks by unloading PCNA which, otherwise, accumulates and persists on DNA, causing a collision with the transcription machinery. Depletion of ATAD5 reduces transcription rates due to PCNA accumulation. Consistent with the role of ATAD5 and RNA helicases in maintaining genomic integrity by regulating R-loops, the corresponding genes were mutated or downregulated in several human tumors
URI
https://pr.ibs.re.kr/handle/8788114/7771
DOI
10.1093/nar/gkaa501
ISSN
0305-1048
Appears in Collections:
Center for Genomic Integrity(유전체 항상성 연구단) > 1. Journal Papers (저널논문)
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