Biology subjects

Haluza, V.

Publications and source records attributed to Haluza, V..

2 recordsLinked to original sources

bioRxiv2024

Tetrameric INTS6-SOSS1 complex facilitates DNA:RNA hybrid autoregulation at double-strand breaks

DNA double strand breaks (DSBs) represent a lethal form of DNA damage that can trigger cell death and initiate oncogenesis. The activity of RNA polymerase II (RNAPII) at the break site is required for efficient DSB repair. However, the regulatory mechanisms governing the transcription cycle at DSBs are not well understood. Here, we show that Integrator complex subunit 6 (INTS6) associates with the trimeric SOSS1 (comprising INTS3, INIP, and hSSB1) to form a tetrameric SOSS1 complex following DNA damage. INTS6 binds to DNA:RNA hybrids and plays a crucial role in Protein Phosphatase 2 (PP2A) recruitment to DSBs, facilitating the dephosphorylation of RNAPII. Furthermore, INTS6 prevents the accumulation of damage-induced RNA transcripts (DARTs) and the stabilization of DNA:RNA hybrids at DSB sites. INTS6 interacts with, and promotes the recruitment of Senataxin (SETX) to DSBs, facilitating the resolution of DNA:RNA hybrids/R-loops. Our results underscore the significance of the SOSS1 complex in the autoregulation of DNA:RNA dynamics and the promotion of efficient DNA repair.

molecular biology↗

bioRxiv2023

Phosphorylated trimeric SOSS1 complex and RNA polymerase II trigger liquid-liquid phase separation at double-strand breaks

The most toxic forms of DNA damage are double-strand breaks (DSBs). We have previously shown that RNA polymerase II (RNAPII), phosphorylated at tyrosine 1 (Y1P) on the C- terminal domain, transcribes RNA at DSBs to promote efficient DNA repair. However, it is still unknown how transcription is regulated at DSBs. Here, we show that the trimeric SOSS1 complex (hSSB1, INTS3, and c9orf80) binds to Y1P RNAPII in response to DNA damage, hSSB1 binds to R-loops, and formation of the SOSS1 complex is required for the coexistence of replication protein A (RPA) and hSSB1 at DSBs. The damage-activated tyrosine kinase c- Abl phosphorylates hSSB1 to enable its binding to Y1P RNAPII and its recruitment to DSBs. Finally, we show both in vitro and in vivo that the SOSS1 complex and RNAPII form dynamic repair compartments at DSBs via liquid-liquid phase separation (LLPS). The loss of the trimeric SOSS1 leads to impaired DNA repair, highlighting its biological importance in the RNA-dependent DNA damage response. TeaserTrimeric SOSS1 complex and transcription contribute to phase separation at double-strand DNA breaks.

molecular biology↗