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  1. Article ; Online: RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity.

    Feng, Sumin / Ma, Sai / Li, Kejiao / Gao, Shengxian / Ning, Shaokai / Shang, Jinfeng / Guo, Ruiyuan / Chen, Yingying / Blumenfeld, Britny / Simon, Itamar / Li, Qing / Guo, Rong / Xu, Dongyi

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 957

    Abstract: 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 ...

    Abstract 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 identify a RIF1-ASF1 histone chaperone complex that promotes changes in high-order chromatin structure to stimulate the NHEJ pathway for DSB repair.
    MeSH term(s) Animals ; BRCA1 Protein/genetics ; BRCA1 Protein/metabolism ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Chickens ; Chromatin/genetics ; Chromatin/metabolism ; DNA End-Joining Repair ; Epistasis, Genetic ; Gene Knockdown Techniques ; Gene Knockout Techniques ; HEK293 Cells ; Humans ; Molecular Chaperones/genetics ; Molecular Chaperones/metabolism ; Telomere-Binding Proteins/genetics ; Telomere-Binding Proteins/metabolism
    Chemical Substances ASF1A protein, human ; ASF1B protein, human ; BRCA1 Protein ; BRCA1 protein, human ; Cell Cycle Proteins ; Chromatin ; Molecular Chaperones ; Rif1 protein, human ; Telomere-Binding Proteins
    Language English
    Publishing date 2022-02-17
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-28588-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Fanconi anemia proteins participate in a break-induced-replication-like pathway to counter replication stress.

    Xu, Xinlin / Xu, Yixi / Guo, Ruiyuan / Xu, Ran / Fu, Congcong / Xing, Mengtan / Sasanuma, Hiroyuki / Li, Qing / Takata, Minoru / Takeda, Shunichi / Guo, Rong / Xu, Dongyi

    Nature structural & molecular biology

    2021  Volume 28, Issue 6, Page(s) 487–500

    Abstract: Fanconi anemia (FA) is a devastating hereditary disease characterized by bone marrow failure (BMF) and acute myeloid leukemia (AML). As FA-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), ICLs are widely assumed to be the lesions ... ...

    Abstract Fanconi anemia (FA) is a devastating hereditary disease characterized by bone marrow failure (BMF) and acute myeloid leukemia (AML). As FA-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), ICLs are widely assumed to be the lesions responsible for FA symptoms. Here, we show that FA-mutated cells are hypersensitive to persistent replication stress and that FA proteins play a role in the break-induced-replication (BIR)-like pathway for fork restart. Both the BIR-like pathway and ICL repair share almost identical molecular mechanisms of 53BP1-BRCA1-controlled signaling response, SLX4- and FAN1-mediated fork cleavage and POLD3-dependent DNA synthesis, suggesting that the FA pathway is intrinsically one of the BIR-like pathways. Replication stress not only triggers BMF in FA-deficient mice, but also specifically induces monosomy 7, which is associated with progression to AML in patients with FA, in FA-deficient cells.
    MeSH term(s) Aneuploidy ; Animals ; Bone Marrow Failure Disorders/etiology ; Cell Line, Transformed ; Chickens ; Chromosome Breakage ; Chromosome Deletion ; Chromosomes, Human, Pair 7/genetics ; DNA Polymerase III/physiology ; DNA Replication/genetics ; Disease Progression ; Fanconi Anemia/genetics ; Fanconi Anemia/metabolism ; Fanconi Anemia Complementation Group Proteins/deficiency ; Fanconi Anemia Complementation Group Proteins/genetics ; Fanconi Anemia Complementation Group Proteins/physiology ; Female ; HCT116 Cells ; HEK293 Cells ; Humans ; Hydroxyurea/pharmacology ; Leukemia, Myeloid, Acute/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Models, Genetic ; Species Specificity ; Tumor Suppressor p53-Binding Protein 1/physiology ; Ubiquitin-Protein Ligases/physiology
    Chemical Substances Fanconi Anemia Complementation Group Proteins ; TP53BP1 protein, human ; Tumor Suppressor p53-Binding Protein 1 ; BRAP protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; POLD3 protein, human (EC 2.7.7.-) ; DNA Polymerase III (EC 2.7.7.7) ; Hydroxyurea (X6Q56QN5QC)
    Language English
    Publishing date 2021-06-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2126708-X
    ISSN 1545-9985 ; 1545-9993
    ISSN (online) 1545-9985
    ISSN 1545-9993
    DOI 10.1038/s41594-021-00602-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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