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RNA Biol. 2016;13(3):272-8. doi: 10.1080/15476286.2016.1142039. Epub 2016 Feb 25.

Bidirectional coupling of splicing and ATM signaling in response to transcription-blocking DNA damage.

Author information

1
a Department of Genetics , Cancer Genomics Netherlands, Erasmus University Medical Center , Rotterdam , The Netherlands.

Abstract

In response to DNA damage cells activate intricate protein networks to ensure genomic fidelity and tissue homeostasis. DNA damage response signaling pathways coordinate these networks and determine cellular fates, in part, by modulating RNA metabolism. Here we discuss a replication-independent pathway activated by transcription-blocking DNA lesions, which utilizes the ATM signaling kinase to regulate spliceosome function in a reciprocal manner. We present a model according to which, displacement of co-transcriptional spliceosomes from lesion-arrested RNA polymerases, culminates in R-loop formation and non-canonical ATM activation. ATM signals in a feed-forward fashion to further impede spliceosome organization and regulates UV-induced gene expression and alternative splicing genome-wide. This reciprocal coupling between ATM and the spliceosome highlights the importance of ATM signaling in the cellular response to transcription-blocking lesions and supports a key role of the splicing machinery in this process.

KEYWORDS:

ATM; Alternative splicing; DDR signaling; DNA damage; R-loops; UV irradiation; spliceosome; transcription

PMID:
26913497
PMCID:
PMC4829274
[Available on 2017-02-25]
DOI:
10.1080/15476286.2016.1142039
[Indexed for MEDLINE]
Free PMC Article

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