hSSB1 interacts directly with the MRN complex stimulating its recruitment to DNA double-strand breaks and its endo-nuclease activity

Richard, Derek J.; Cubeddu, Liza; Urquhart, Aaron; Bain, Amanda L.; Bolderson, Emma; Menon, Dinoop Ravindran; White, Malcolm F.; Khanna, Kum Kum

doi:10.1093/nar/gkq1340

Cited by 77 publications

(122 citation statements)

References 29 publications

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“…In mammalian cells, the OB-fold proteins RPA and hSSB1 have been predicted to be the homologs of bacterial ssDNA binding protein (17). However, it has been shown that the functions of hSSB1 and RPA in DNA damage may be distinct (17,18,21,22,24). Unlike RPA or other known OB-fold proteins, the affinity of hSSB1 for ssDNA is relatively low.…”

Section: Ints3mentioning

confidence: 99%

“…More recent studies have shown that hSSB1 is not only rapidly recruited to DSBs, but also interacts with the MRN complex, and may facilitate its recruitment to the DNA damage sites (18,19). This interaction indicates that hSSB1 is likely one of the earliest DNA damage repair proteins recruited to DNA damage sites.…”

mentioning

confidence: 95%

“…INTS3 is a well-folded protein and previously identified as a member in the INTS complex that regulates RNA processing and gene transcription (25). Like hSSB1, INTS3 is also quickly relocated to DNA lesions in response to DSBs and participates in DSB repair (21-24).More recent studies have shown that hSSB1 is not only rapidly recruited to DSBs, but also interacts with the MRN complex, and may facilitate its recruitment to the DNA damage sites (18,19). This interaction indicates that hSSB1 is likely one of the earliest DNA damage repair proteins recruited to DNA damage sites.…”

mentioning

confidence: 99%

“…Previous studies have shown that human ssDNA-binding protein 1 (hSSB1) plays a key role in DDR (17)(18)(19)(20). hSSB1 is a 211-residue polypeptide containing an oligonucleotide/oligosaccharide-binding (OB) fold at the N terminus.…”

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confidence: 99%

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The oligonucleotide/oligosaccharide-binding fold motif is a poly(ADP-ribose)-binding domain that mediates DNA damage response

Zhang

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Oligonucleotide/oligosaccharide-binding (OB) fold is a ssDNA or RNA binding motif in prokaryotes and eukaryotes. Unexpectedly, we found that the OB fold of human ssDNA-binding protein 1 (hSSB1) is a poly(ADP ribose) (PAR) binding domain. hSSB1 exhibits highaffinity binding to PAR and recognizes iso-ADP ribose (ADPR), the linkage between two ADPR units. This interaction between PAR and hSSB1 mediates the early recruitment of hSSB1 to the sites of DNA damage. Mutations in the OB fold of hSSB1 that disrupt PAR binding abolish the relocation of hSSB1 to the sites of DNA damage. Moreover, PAR-mediated recruitment of hSSB1 is important for early DNA damage repair. We have screened other OB folds and found that several other OB folds also recognize PAR. Taken together, our study reveals a PAR-binding domain that mediates DNA damage repair.G enomic integrity is constantly challenged by various types of DNA damage, which are induced by DNA replication errors, environmental hazards, and other genotoxic stress. In response to this stress, cells activate an evolutionarily conserved pathway termed the DNA damage response (DDR), to orchestrate various cellular responses for maintaining genomic stability (1-3). It has been shown that poly(ADP ribosyl)ation plays an important role in DDR (4-6). Upon DNA damage induction, poly(ADP ribose) (PAR) polymerases (PARPs), such as PARP1, the founding member of the PARP family, rapidly detect DNA breaks, including single-strand breaks (SSBs) and double-strand breaks (DSBs), and activate PAR synthesis at or adjacent to DNA lesions (7,8). Recent evidence suggests that DNA damage-induced PAR may serve as a docking signal to recruit DDR factors to DNA lesions (7-14). For example, our recent study showed that the BRCT domains of BARD1 and NBS1 recognize PAR, which facilitates the rapid recruitment of the BRCA1/BARD1 complex and NBS1 to the site of DNA damage (15, 16). These results indicate that other DDR factors may also be recruited to DNA damage sites by PAR. Thus, it is important to identify other "readers" of PAR to elucidate the molecular mechanism of PAR in DDR.Previous studies have shown that human ssDNA-binding protein 1 (hSSB1) plays a key role in . hSSB1 is a 211-residue polypeptide containing an oligonucleotide/oligosaccharide-binding (OB) fold at the N terminus. Following DNA damage, hSSB1 quickly relocates to DNA damage sites and regulates foci formation of other DNA damage repair proteins, such as BRCA1 and RAD51 (17,(21)(22)(23)(24). Thus, depletion of hSSB1 impairs the repair of DSBs. In response to DNA damage, hSSB1 is phosphorylated by ATM and regulates ATM-dependent cell cycle checkpoint activation (17,(21)(22)(23)(24). By protein affinity purifications, hSSB1 was shown to tightly associate with other proteins, such as INTS3, forming a multisubunit complex (21-24). INTS3 is a well-folded protein and previously identified as a member in the INTS complex that regulates RNA processing and gene transcription (25). Like hSSB1, INTS3 is also quickly relocated to DNA lesions in r...

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Section: Ints3mentioning

confidence: 99%

mentioning

confidence: 95%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The oligonucleotide/oligosaccharide-binding fold motif is a poly(ADP-ribose)-binding domain that mediates DNA damage response

Zhang

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, the SOSS complex (INTS3-hSSB1-C9orf80) has been shown to play key roles in DNA damage response and DNA repair [22][23][24][25]. Mechanistically, hSSB1 has recently been shown to (1) be required for the efficient recruitment of the MRN complex, (2) bind directly with NBS1 and (3) stimulate the endonuclease activity of the MRN complex [26,27]. Moreover, we have recently shown that hSSB1 regulates cell cycle progression and DNA damage checkpoints by modulating the stability of p21 in cancer cells [28].…”

Section: Introductionmentioning

confidence: 99%

hSSB1 regulates both the stability and the transcriptional activity of p53

Chen

et al. 2012

Cell Res

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The tumor suppressor p53 is essential for several cellular processes that are involved in the response to diverse genotoxic stress, including cell cycle arrest, DNA repair, apoptosis and senescence. Studies of the regulation of p53 have mostly focused on its stability and transactivation; however, new regulatory molecules for p53 have also been frequently identified. Here, we report that human ssDNA binding protein SSB1 (hSSB1), a novel DNA damageassociated protein, can interact with p53 and protect p53 from ubiquitin-mediated degradation. Furthermore, hSSB1 also associates with the acetyltransferase p300 and is required for efficient transcriptional activation of the p53 target gene p21 by affecting the acetylation of p53 at lysine382. Functionally, the hSSB1 knockdown-induced abrogation of the G2/M checkpoint is partially dependent on p53 or p300. Collectively, our results indicate that hSSB1 may regulate DNA damage checkpoints by positively modulating p53 and its downstream target p21.

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The molecular details of a novel phosphorylation‐dependent interaction between MRN and the SOSS complex

El‐Kamand,

Adams,

Matthews

et al. 2023

Protein Science

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The repair of double‐strand DNA breaks (DSBs) by homologous recombination is crucial in the maintenance of genome integrity. While the key role of the Mre11‐Rad50‐ Nbs1 (MRN) complex in repair is well known, hSSB1 (SOSSB, OBFC2B), one of the main components of the sensor of single‐stranded DNA (SOSS) protein complex, has also been shown to rapidly localise to DSB breaks and promote repair. We have previously demonstrated that hSSB1 binds directly to Nbs1, a component of the MRN complex, in a DNA damage‐independent manner. However, recruitment of the MRN complex has also been demonstrated by an interaction between Integrator Complex Subunit 3 (INTS3; also known as SOSSA), another member of the SOSS complex, and Nbs1. In this study, we utilise a combined approach of in silico, biochemical and functional experiments to uncover the molecular details of INTS3 binding to Nbs1. We demonstrate that the FHA domain of Nbs1 interacts with INTS3 via phosphorylation‐dependent binding to INTS3 at Threonine 592, with contributions from Serine 590. Based on these data, we propose a model of MRN recruitment to a DSB via INTS3.This article is protected by copyright. All rights reserved.

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hSSB1 interacts directly with the MRN complex stimulating its recruitment to DNA double-strand breaks and its endo-nuclease activity

Cited by 77 publications

References 29 publications

The oligonucleotide/oligosaccharide-binding fold motif is a poly(ADP-ribose)-binding domain that mediates DNA damage response

The oligonucleotide/oligosaccharide-binding fold motif is a poly(ADP-ribose)-binding domain that mediates DNA damage response

hSSB1 regulates both the stability and the transcriptional activity of p53

The molecular details of a novel phosphorylation‐dependent interaction between MRN and the SOSS complex

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