Hirakawa, M. | Search bioRxiv

bioRxiv2023

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

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, which is an essential step in HR, without affecting the expression of HR factors. In the promotion of resection, SART1 is epistatic with BRCA1, an HR factor known to promote resection. Mechanistically, SART1 cooperates with BRCA1 to counteract the resection blockade posed by 53BP1 and RIF1. Moreover, SART1 is required for recruitment of the HR-promoting portion of BRCA1 to DSBs. Laser microirradiation experiments revealed that SART1 is recruited to DSBs in a BRCA1-dependent manner, and that the arginine/serine (RS)-rich domain is required for SART1 recruitment to DSBs. We also obtained evidence that SART1 is involved in transcription-associated HR together with BRCA1. 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, thereby promoting faithful HR repair of such DSBs and suppressing genome instability.

cell biology↗

bioRxiv2023

Externally provided rewards increase internal preference, but not as much as preferred ones without extrinsic rewards

It is well known that preferences are formed through choices, known as choice-induced preference change (CIPC). However, whether value learned through externally provided rewards influences the preferences formed through CIPC remains unclear. To address this issue, we used tasks for decision-making guided by reward provided by the external environment (externally guided decision-making; EDM) and for decision-making guided by ones internal preference (internally guided decision-making; IDM). In the IDM task, we presented stimuli with learned value in the EDM and novel stimuli to examine whether the value in the EDM affects preferences. Stimuli reinforced by rewards given in the EDM were reflected in the IDMs initial preference and further increased through CIPC in the IDM. However, such stimuli were not as strongly preferred as the most preferred novel stimulus in the IDM, indicating the superiority of intrinsically learned values (SIV). The underlying process of this phenomenon is discussed in terms of the fundamental self-hypothesis. Author SummaryWe make decisions based on internal value criteria, which are individual preferences, or based on external value criteria, which are the values learned from the external environment. Although it is known that values are learned in both types of decisions, is there a difference in the nature of these values? Our study uses simulation and fits human behavioral data to address this question. The results showed that stimuli that were learned to be highly valued because of external feedback became preferred in subsequent preference judgments. However, it is interesting to note that such stimuli were not chosen as much as stimuli that were preferred without influence from the external environment. This finding suggests that values formed through ones own criteria have characteristics distinct from those formed through external environmental influence. Our findings promote an integrated understanding of the decision-making process.

animal behavior and cognition↗