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@ARTICLE{Wagner:294321,
author = {R. Wagner$^*$ and L. Arnetzl$^*$ and T. Britto-Borges and
A. Heit-Mondrzyk$^*$ and A. Bakr$^*$ and E. Sollier$^*$ and
N. A. Gkatza and J. Panten$^*$ and S. Delaunay$^*$ and D.
Sohn$^*$ and P. Schmezer$^*$ and D. T. Odom$^*$ and K.
Müller-Decker and C. Plass$^*$ and C. Dieterich and P.
Lutsik$^*$ and S. Bornelöv and M. Frye$^*$},
title = {{SRSF}2 safeguards efficient transcription of {DNA} damage
and repair genes.},
journal = {Cell reports},
volume = {43},
number = {11},
issn = {2211-1247},
address = {[New York, NY]},
publisher = {Elsevier},
reportid = {DKFZ-2024-02154},
pages = {114869},
year = {2024},
note = {#EA:A350#LA:A350#},
abstract = {The serine-/arginine-rich splicing factor 2 (SRSF2) plays
pivotal roles in pre-mRNA processing and gene transcription.
Recurrent mutations, particularly a proline-to-histidine
substitution at position 95 (P95H), are common in neoplastic
diseases. Here, we assess SRSF2's diverse functions in
squamous cell carcinoma. We show that SRSF2 deletion or
homozygous P95H mutation both cause extensive DNA damage
leading to cell-cycle arrest. Mechanistically, SRSF2
regulates efficient bi-directional transcription of DNA
replication and repair genes, independent from its function
in splicing. Further, SRSF2 haploinsufficiency induces DNA
damage without halting the cell cycle. Exposing mouse skin
to tumor-promoting carcinogens enhances the clonal expansion
of heterozygous Srsf2 P95H epidermal cells but unexpectedly
inhibits tumor formation. To survive carcinogen treatment,
Srsf2 P95H+/- cells undergo substantial transcriptional
rewiring and restore bi-directional gene expression. Thus,
our study underscores SRSF2's importance in regulating
transcription to orchestrate the cell cycle and the DNA
damage response.},
keywords = {CP: Cancer (Other) / CP: Molecular biology (Other) / DNA
damage (Other) / DNA repair (Other) / DNA replication
(Other) / Transcription (Other) / bi-directional promoters
(Other) / epithelia (Other) / skin (Other)},
cin = {A350 / B370 / B270},
ddc = {610},
cid = {I:(DE-He78)A350-20160331 / I:(DE-He78)B370-20160331 /
I:(DE-He78)B270-20160331},
pnm = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
pid = {G:(DE-HGF)POF4-311},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39446588},
doi = {10.1016/j.celrep.2024.114869},
url = {https://inrepo02.dkfz.de/record/294321},
}