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Role of the SAF-A ATPase and RGG domains in X inactivation, transcription, splicing, and cell proliferation.

ABSTRACT: SAF-A/HNRNPU is conserved throughout vertebrates and has emerged as an important factor regulating a multitude of nuclear functions, including lncRNA localization, gene expression, and splicing. SAF-A has several functional domains, including a central ATPase domain and a C-terminal RGG domain. In this study we tested for the role of the ATP binding, ATP hydrolysis and RNA binding in X chromosome inactivation, protein dynamics, gene expression, splicing, and cell proliferation. Here we show that the ATPase and RGG domains are required to maintain XIST RNA localization and XIST-dependent histone modifications on the inactive X chromosome, to execute normal protein dynamics, and to maintain normal cell proliferation. We found that the ATPase and RGG domains are not required to maintain gene expression but play a major role in mRNA splicing. We propose a model whereby RNA binding, ATP binding and ATP hydrolysis promote SAF-A interaction with nascent RNA to promote normal mRNA splicing and XIST localization and function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309811 | GEO | 2026/02/26

REPOSITORIES: GEO

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Project description:SWI/SNF-family chromatin remodelling complexes conduct nucleosome sliding and ejection to provide DNA-binding proteins access to their sites in chromatin. RSC is an essential and abundant SWI/SNF-family chromatin remodeller from S. cerevisiae that both slides and ejects nucleosomes. However, how ejection versus sliding is chosen, regulated and implemented by any remodeller remains largely unknown. The RSC catalytic subunit Sth1 conducts ATP-dependent DNA translocation, pumping DNA around the nucleosome, providing a property that might underlie both sliding and ejection. Sth1 shares with other SWI/SNF-family ATPases direct binding to two nuclear actin-related proteins (ARPs), but how ARPs impact DNA translocation, sliding and ejection is unknown. Here, we reveal that nucleosome ejection by RSC requires ARPs, and that ARPs improve ‘coupling’ – the efficiency of DNA translocation by Sth1 relative to ATP hydrolysis – thus, enhancing DNA translocation. We further characterize two domains within Sth1 (termed PTH and P1), showing they separately regulate ATP hydrolysis or ‘coupling’, respectively. Interestingly, gain-of-function PTH or P1 mutations suppress arpΔ lethality, and improve ATPase or coupling activities, enabling Sth1 to efficiently slide and eject nucleosomes without ARPs. Moreover, PTH mutations greatly improved DNA translocation velocity. Overall, our results provide a logic for regulating nucleosome sliding versus ejection: both modes involve DNA translocation, but ejection requires a higher magnitude. Here, low-to-moderate ATPase and coupling activity integrate to confer low-to-moderate sliding, whereas high ATPase and/or coupling combine to provide efficient and rapid DNA translocation, consistent with the simultaneous rupture of multiple histone-DNA contacts, causing histone loss/ejection. Our discovery of an ARP module and regulatory domains that regulate sliding and ejection suggests a mechanistic platform through which activators and histone epitopes may guide the remodelling outcome of SWI/SNF-family chromatin remodellers.

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Role of the SAF-A ATPase and RGG domains in X inactivation, transcription, splicing, and cell proliferation.

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