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ASF1 acts with RIF1 to promote DNA end-joining in BRCA1 deficient cells

ABSTRACT: RIF1 acts downstream of 53BP1 to coordinate DNA double strand break repair pathway choice between non-homologous end joining (NHEJ) and homologous recombination (HR). Here we identified ASF1 as an endogenous RIF1-associated protein. We showed that ASF1 forms complex with RIF1 and regulates RIF1-dependent functions in DNA damage response.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Zhen Chen

LAB HEAD: Junjie Chen

PROVIDER: PXD027727 | Pride | 2022-06-09

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	03212019_Zhen_Mengfan_ASF1A_4.msf	Msf
	03212019_Zhen_Mengfan_ASF1A_4.raw	Raw
	03212019_Zhen_Mengfan_ASF1B_11.msf	Msf
	03212019_Zhen_Mengfan_ASF1B_11.raw	Raw
	09232018_RIF1_SFB_Chr_73.msf	Msf

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1 - 5 of 9

Publications

Histone chaperone ASF1 acts with RIF1 to promote DNA end joining in BRCA1-deficient cells.

Tang Mengfan M Chen Zhen Z Wang Chao C Feng Xu X Lee Namsoo N Huang Min M Zhang Huimin H Li Siting S Xiong Yun Y Chen Junjie J

The Journal of biological chemistry 20220425 6

Replication timing regulatory factor 1 (RIF1) acts downstream of p53-binding protein 53BP1 to inhibit the resection of DNA broken ends, which plays critical roles in determining the DNA double-strand break repair pathway choice between nonhomologous end joining and homologous recombination (HR). However, the mechanism by which this choice is made is not yet clear. In this study, we identified that histone chaperone protein ASF1 associates with RIF1 and regulates RIF1-dependent functions in the D ...[more]

PMID: 35472331

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RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity

Project description:The 53BP1-RIF1 pathway antagonizes resection of DNA broken ends and confers PARP inhibitor sensitivity on BRCA1-mutated tumors. However, it is unclear how this pathway suppresses initiation of resection. Here, we identify ASF1 as a partner of RIF1 via an interacting manner similar to its interactions with histone chaperones CAF-1 and HIRA. ASF1 is recruited to distal chromatin flanking DNA breaks by 53BP1-RIF1 and promotes non-homologous end joining (NHEJ) using its histone chaperone activity. Epistasis analysis shows that ASF1 acts in the same NHEJ pathway as RIF1, but via a parallel pathway with the shieldin complex, which suppresses resection after initiation. Moreover, defects in end resection and homologous recombination (HR) in BRCA1-deficient cells are largely suppressed by ASF1 deficiency. Mechanistically, ASF1 compacts adjacent chromatin by heterochromatinization to protect broken DNA ends from BRCA1-mediated resection. Taken together, our findings identified a RIF1-ASF1 histone chaperone complex that promotes changes in high-order chromatin structure to stimulate the NHEJ pathway for DSB repair.

2022-02-04 | PXD031311 | Pride

CTCF cooperates with CtIP to drive homologous recombination repair of double-strand breaks

Project description:The pleiotropic CCCTC-binding factor (CTCF) plays a role in homologous recombination (HR) repair of DNA double-strand breaks (DSBs). However, the precise mechanistic role of CTCF in HR remains largely unclear. Here, we show that CTCF engages in DNA end resection, which is the initial, crucial step in HR, through its interactions with MRE11 and CtIP. Depletion of CTCF profoundly impairs HR and attenuates CtIP recruitment at DSBs. CTCF physically interacts with MRE11 and CtIP and promotes CtIP recruitment to sites of DNA damage. Subsequently, CTCF facilitates DNA end resection to allow HR, in conjunction with MRE11-CtIP. Notably, the zinc finger domain of CTCF binds to both MRE11 and CtIP and enables proficient CtIP recruitment, DNA end resection, and HR. The N-terminus of CTCF is able to bind to only MRE11 and its C-terminus is incapable of binding to MRE11 and CtIP, thereby resulting in compromised CtIP recruitment, DSB resection, and HR. Overall, this suggests an important function of CTCF in DNA end resection through the recruitment of CtIP at DSBs. Collectively, our findings identify a critical role of CTCF at the first control point in selecting the HR repair pathway

2019-11-12 | PXD014441 | Pride

Comprehensive analysis of the host-virus interactome of SARS-CoV-2

Project description:Host-virus protein-protein interaction is the key component of SARS-CoV-2 life cycle, which can be targeted for therapeutic intervention. Thus, we conducted a comprehensive interactome study between the virus and host cell using tandem affinity purification (TAP) and BioID2 labeling strategies. In addition, we compared the interactomes of two key SARS-CoV-2 encoded viral proteins, NSP1 and N protein, to the interactomes of their counterparts in other human coronaviruses.

2021-06-29 | PXD023209 | Pride

USP11 deubiquitinates monoubiquitinated SPRTN to repair DNA-protein crosslinks

Project description:DNA-protein crosslinks (DPCs) are toxic DNA lesions that interfere with DNA metabolic processes such as replication, transcription, and recombination. SPRTN is a replication-coupled DNA-dependent metalloprotease that degrades proteins crosslinked to DNA to promote DPC repair. SPRTN function is tightly regulated by a monoubiquitin switch that controls SPRTN chromatin accessibility during DPC repair. The deubiquitinase regulating SPRTN function in DPC repair is unknown. To identify SPRTN modifiers, we performed tandem-affinity purification and mass spectrometry (TAP-MS) analysis of SFB (S-FLAG-streptavidin binding peptide)-tagged SPRTN expressed in HEK 293T cells. We screened the MS list for proteins that are known to function as a deubiquitinase and identified only one potential SPRTN modifier, USP11 deubiquitinase. A reciprocal TAP-MS analysis of SFB-USP11 expressed in HEK 293T cells treated with camptothecin (CPT) immunoprecipitated SPRTN. USP11 interacts with SPRTN and cleaves monoubiquitinated SPRTN in cells and in vitro. USP11 depletion impaired SPRTN deubiquitination in response to formaldehyde-induced DPCs. Loss of USP11 causes an accumulation of unrepaired DPCs and cellular hypersensitivity to treatment with DPC-inducing agents. Our findings elucidates the function of USP11 in the regulation of SPRTN monoubiquitination and SPRTN-mediated DPC repair.

2021-04-01 | PXD019923 | Pride

HOXB13 WT and G84E mass spectrometry

Project description:To identify potential cofactors of HOXB13 in suppressing lipogenic programs in prostate cancer cells, we performed tandem affinity purification followed by mass spectrometry analysis of WT and G84E HOXB13 expressed in LNCaP cells. Out of the HOXB13-enriched proteins are previously reported interactors such as AR and its cofactors FOXA1, GATA2, and NKX3. However, these interactions were not disrupted by G84E as compared to WT HOXB13. Interestingly, we found strong interactions of HOXB13 with HDAC1/3 and their corepressors NCoR1/2 and TBL1X. Notably, these interactions were drastically reduced by G84E mutation.

2023-03-11 | PXD030810 | Pride

Genome-wide distribution of UHRF2 and ZNF618 in 293T cells.

Project description:We have identified ZNF618 as a novel binding partner of UHRF2. We have found that UHRF2 and ZNF618 co-localize at many genomic loci. Examination of genome-wide distribution of SFB-tagged UHRF2 and ZNF618 in 293T cells using ChIP-seq.

2016-05-31 | E-GEOD-80037 | biostudies-arrayexpress

Genome-wide targets of conserved histone chaperone Asf1 in budding yeast

Project description:Asf1, through its histone chaperone activity, helps chromatin closing/opening during DNA replication, repair, recombination and transcription. Despite extensive research on Asf1-mediated physiological functions, a genome-wide localization map is lacking, limiting our knowledge of chromosomal features targeted by Asf1. We present a high-resolution genome-wide map of Asf1, localizing at essentially all pol III-transcribed genes, highly active pol II-transcribed genes and heterochromatic features. Pol III-transcribed genes are negatively regulated by Asf1, whereas pol II genes are regulated indirectly by Asf1-dependent H3K56 acetylation. Interestingly, Asf1 localization along yeast chromosomes shows nearly identical distribution to that of the condensin complex, predicting a functional overlap in chromosome architecture and genome organization. ChIP-seq analysis of Asf1 targets using a yeast strain that expresses an 18-Myc tag fused to the C-terminus of ASF1. Two biological replicates and one mock/control were performed. The Illumina GAII was used. ChIP-seq reads are aligned to the budding yeast sacCer3 (2011) assembly.

2014-07-30 | E-GEOD-40717 | biostudies-arrayexpress

Identification of novel 53BP1 associated proteins

Project description:We used homologous recombination based CRISPR Knock-in strategy to insert a SFB tag at C terminal of 53BP1 in 293T cells. We performed tandem affinity purification of endogenous 53BP1 in both soluble and chromatin fraction to uncover known and new 53BP1 binding proteins which might play roles in DNA damage response. We identified and examined FOXK1 for its role in DNA damage response through the interaction with 53BP1 mainly in soluble fraction.

2021-09-09 | PXD020090 | Pride

Interactome of ferroptosis pathways genes

Project description:We conducted a proteomic interactome analysis of well-known regulators of ferroptosis, ACSL4, LPCAT3, ALOX12, ALOX15, PEBP1, NCOA4, GCH1, FSP1, DHODH, SLC7A11, GCLC, GCLM, GSS, and GPX4. Take LPCAT3 as an example, we uncovered an opposing role of its binding protein CEPT1 in suppressing ferroptosis.

2024-10-17 | PXD035146 | Pride

Affinity Purification experiments for 24 human Bromodomain proteins involved in DNA repair and genome integrity (part 1 of 2).

Project description:Bromodomain proteins (BRD) are key chromatin regulators of genome function and stability, as well as therapeutic targets in cancer. In our associated publication (doi:10.1101/gad.331231.119) we systematically delineate the contribution of human BRD proteins for genome stability and DNA double-strand break (DSB) repair using cell-based assays and proteomic interaction network analysis. These AP-MS experiments were performed in order to construct a protein interaction network for the 24 BRDs we identified as promoters of DNA repair and/or genome integrity: BAZ1B, BRD1, BRD2, BRD3, BRD4, BRD8, BRD9, BRPF3, BRWD3, CECR2, EP300, GCN5/KAT2A, PCAF/KAT2B, PHIP, SMARCA2, SP100, SP110, SP140, TAF1, TRIM24, TRIM28, TRIM33, TRIM66, ZMYND8. In combination with cell based assays, we identified a BRD-reader function of PCAF that bound TIP60-mediated histone acetylations at DSBs to recruit a DUB complex to deubiquitylate histone H2BK120, to allow direct acetylation by PCAF and repair of DSBs by homologous recombination. We also discovered the bromo-and-extra-terminal (BET) BRD proteins, BRD2 and BRD4, as negative regulators of transcription-associated RNA-DNA hybrid (R-Loop) as inhibition of BRD2 or BRD4 increased R-loop formation, which generated DSBs. These breaks were reliant on Topoisomerase II and BRD2 directly bound and activated Topoisomerase I, a known restrainer of R-loops. Thus, comprehensive interactome and functional profiling of BRD proteins revealed new homologous recombination and genome stability pathways, providing a strategy to understand genome maintenance by BRD proteins and the effects of their pharmacological inhibition. This accession provides AP-MS experiment files for the following subset of 18 BRDs: BAZ1B, BRD1, BRD2, BRD3, BRD4, BRD8, BRPF3, BRWD3, CECR2, PHIP, SMARCA2, SP100, SP110, TAF1, TRIM24, TRIM33, TRIM66, ZMYND8, as well as their associated controls (Input, Mock, and SBP-tagged NLS).

2019-12-12 | PXD016700 | Pride

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