Involvement of the splicing factor SART1 in the BRCA1-dependent homologous 
recombination repair of DNA double-strand breaks

Ozaki, Kie; Kato, Reona; Yasuhara, Takaaki; Uchihara, Yuki; Hirakawa, Miyako; Abe, Yu; Shibata, Hiroki; Kawabata-Iwakawa, Reika; Shakayeva, Aizhan; Kot, Palina; Miyagawa, Kiyoshi; Suzuki, Keiji; Matsuda, Naoki; Shibata, Atsushi; Yamauchi, Motohiro

doi:10.1038/s41598-024-68926-2

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Involvement of the splicing factor SART1 in the BRCA1-dependent homologous recombination repair of DNA double-strand breaks

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Kot, Palina
IMPRS, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Ozaki, K., Kato, R., Yasuhara, T., Uchihara, Y., Hirakawa, M., Abe, Y., et al. (2024). Involvement of the splicing factor SART1 in the BRCA1-dependent homologous recombination repair of DNA double-strand breaks. SCIENTIFIC REPORTS, 14(1): 18455. doi:10.1038/s41598-024-68926-2.

Cite as: https://hdl.handle.net/21.11116/0000-0010-0892-0

Abstract

Although previous studies have reported that pre-mRNA splicing factors
(SFs) are involved in the repair of DNA double-strand breaks (DSBs) via
homologous recombination (HR), their exact role in promoting HR remains
poorly understood. Here, we showed that SART1, an SF upregulated in
several types of cancer, promotes DSB end resection, an essential first
step of HR. The resection-promoting function of SART1 requires
phosphorylation at threonine 430 and 695 by ATM/ATR. SART1 is recruited
to DSB sites in a manner dependent on transcription and its RS domain.
SART1 is epistatic with BRCA1, a major HR factor, in the promotion of
resection, especially transcription-associated resection in the G2
phase. SART1 and BRCA1 accumulate at DSB sites in an interdependent
manner, and epistatically counteract the resection blockade posed by
53BP1 and RIF1. Furthermore, chromosome analysis demonstrated that SART1
and BRCA1 epistatically suppressed genomic alterations caused by DSB
misrepair in the G2 phase. Collectively, these results indicate that
SART1 and BRCA1 cooperatively facilitate resection of DSBs arising in
transcriptionally active genomic regions in the G2 phase, thereby
promoting faithful repair by HR, and suppressing genome instability.