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Li Et Al., Sci DNA polymerase α interacts with H3-H4 and facilitates the transfer of parental histones to lagging strands Zhiming Li, Xu Hua, Albert Serra-Cardona, Xiaowei Xu, Songlin Gan, Hui Zhou, Wen-Si Yang, Chun-Long Chen, Rui-Ming Xu, Zhiguo Zhang To cite this version: Zhiming Li, Xu Hua, Albert Serra-Cardona, Xiaowei Xu, Songlin Gan, et al.. DNA polymerase α interacts with H3-H4 and facilitates the transfer of parental histones to lagging strands. Science Advances , American Association for the Advancement of Science (AAAS), 2020, 6 (35), pp.eabb5820. 10.1126/sciadv.abb5820. hal-03015005 HAL Id: hal-03015005 https://hal.archives-ouvertes.fr/hal-03015005 Submitted on 24 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. SCIENCE ADVANCES | RESEARCH ARTICLE MOLECULAR BIOLOGY Copyright © 2020 The Authors, some a rights reserved; DNA polymerase interacts with H3-H4 and facilitates exclusive licensee American Association the transfer of parental histones to lagging strands for the Advancement Zhiming Li1,2,3,4*, Xu Hua1,2,3,4*, Albert Serra-Cardona1,2,3,4*, Xiaowei Xu1,2,3,4*, Songlin Gan5,6, of Science. No claim to 1,2,3,4 5,6 7,8 5,6 1,2,3,4† original U.S. Government Hui Zhou , Wen-Si Yang , Chun-long Chen , Rui-Ming Xu , Zhiguo Zhang Works. Distributed under a Creative How parental histones, the carriers of epigenetic modifications, are deposited onto replicating DNA remains Commons Attribution poorly understood. Here, we describe the eSPAN method (enrichment and sequencing of protein-associated NonCommercial nascent DNA) in mouse embryonic stem (ES) cells and use it to detect histone deposition onto replicating DNA License 4.0 (CC BY-NC). strands with a relatively small number of cells. We show that DNA polymerase a (Pol a), which synthesizes short primers for DNA synthesis, binds histone H3-H4 preferentially. A Pol a mutant defective in histone binding in vitro impairs the transfer of parental H3-H4 to lagging strands in both yeast and mouse ES cells. Last, dysregulation of both coding genes and noncoding endogenous retroviruses is detected in mutant ES cells defective in parental histone transfer. Together, we report an efficient eSPAN method for analysis of DNA replication–linked processes a in mouse ES cells and reveal the mechanism of Pol in parental histone transfer. Downloaded from INTRODUCTION Cdc45­MCM­GINS (CMG) at two replication forks, which travel Faithful duplication of both genetic and epigenetic information is bidirectionally on leading strand templates and unwind the double­ fundamental to the reproduction and evolution of all living organisms. stranded template DNA. DNA polymerase a (Pol a) then generates Nucleosome, the basic unit of eukaryotic chromatin, is composed of a primer to initiate DNA synthesis at both strands, with DNA Pol e http://advances.sciencemag.org/ an octamer of histones wrapped around with ~147–base pair (bp) synthesizing most of the leading strands and Pol d replicating the DNA. Posttranslational modifications (PTMs) of histones play lagging strands or Okazaki fragments (14). important roles in many cellular processes including gene transcrip­ During DNA replication, nucleosomes ahead each fork are rapidly tion and DNA replication (1). Several histone PTMs, including trimethyl­ disassembled to allow for efficient DNA synthesis. Immediately fol­ ation of H3 lysine 9 (H3K9me3) and lysine 27 (H3K27me3), have been lowing replication, replicated DNA is assembled into nucleosomes shown to be transmitted to daughter cells during mitosis, even through by two pathways, de novo deposition of newly synthesized H3­H4 meiosis, to maintain gene expression states (2–5). Moreover, nucleo­ and the transfer of parental histone H3­H4 tetramers. In general, some positions of parental histones are preserved following DNA rep­ nucleosome assembly is a step­wise process with the deposition of lication in both yeast and likely in mouse embryonic stem (ES) cells H3­H4 tetramers first and followed by rapid deposition of H2A­ (6, 7). However, how epigenetic information encoded by histone modi­ H2B. It is known that nascent H3­H4 is deposited with the help of on August 28, 2020 fications is inherited during mitotic cell divisions is largely unknown. various histone chaperones (15, 16). For example, in yeast, nascent Eukaryotic DNA replication initiates at specific genomic sites histone H3­H4 dimer is escorted by Asf1 for acetylation of lysine 56 during S phase in a highly orchestrated process (8, 9). In budding (H3K56ac) by Rtt109 (17, 18). Asf1 then hands over H3­H4 dimers yeast, DNA replication initiates at well­defined adenine­ and thymine-­ to downstream chaperones including the CAF­1 (chromatin assembly rich (AT­rich) auto nomously replicating sequences. In contrast, factor 1) complex, which deposit nascent (H3­H4)2 tetramers for replication origins in mammalian cells lack consensus sequence and nucleosome formation (15). The transfer of parental histones, which site­specific information (10). Instead, most of DNA replication origins guides the re­establishment of epigenetic landscape (19), however, in higher eukaryotic cells initiate as broad initiation zones (11–13). is much less understood. Recently, several replisome components During G1 phase, these origins are recognized by the origin recogni­ are shown to harbor histone chaperone activities and facilitate the tion complex, which loads two heterohexamers of minichromosome transfer of parental H3­H4 onto replicating DNA strands. For maintenance (MCM) proteins (MCM2­7) to form the pre­replication instance, using the eSPAN (enrichment and sequencing of protein­ complex. The MCM2­7 hexamers are subsequently activated in associated nascent DNA) method in budding yeast, Dpb3 and early S phase and form two active replicative helicases consisting of Dpb4, two subunits of Pol e, have been shown to interact with H3­H4 and promote parental histone transfer to leading strand (20). More­ over, human POLE3 and POLE4, the functional homologs of Dpb3 and 1 Institute for Cancer Genetics, Columbia University Irving Medical Center, Dpb4, display histone chaperone activity in vitro (21). MCM2, a subunit New York, NY 10032, USA. 2Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. 3Department of Pediatrics, of the MCM helicase, contains a conserved histone­binding motif Columbia University Medical Center, New York, NY 10032, USA. 4Department of (HBM) at its N terminus (22–24). Mcm2 mutations defective in histone Genetics and Development, Columbia University Medical Center, New York, NY binding show defects in the transfer of parental histones to lagging 10032, USA. 5National Laboratory of Biomacromolecules, Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese strands in budding yeast (25). Using SCAR­seq (sister chromatids Academy of Sciences, Beijing 100101, China. 6School of Life Science, University of after replication by DNA sequencing), a method that uses the same Chinese Academy of Sciences, Beijing 100049, China. 7Curie Institute, PSL Research principle as eSPAN, it has been shown that MCM2 mutant defective 8 University, CNRS UMR 3244, F-75005, Paris, France. Sorbonne University, F-75005 in histone binding in mouse ES cells also show defects in the transfer Paris, France. *These authors contributed equally to this work. of modified parental histones (26), indicating a conserved role of †Corresponding author. Email: [email protected] MCM2 in parental histone transfer. Li et al., Sci. Adv. 2020; 6 : eabb5820 26 August 2020 1 of 14 SCIENCE ADVANCES | RESEARCH ARTICLE The active CMG complex travels along the leading strand tem­ Recently, other laboratories have shown that the CUT&Tag/ACT­ plate with the N termini of MCM subunits facing the parental seq can generate the same information as ChIP­seq but with a much nucleosomes (27–29). In addition, the CMG helicase is connected smaller number of cells (33, 34). Therefore, we replaced the ChIP to lagging strands through adaptor protein Ctf4, which forms a homo­ step of the eSPAN procedure with a modified CUT&Tag/ACT­seq trimeric complex and interacts with GINS and Pol1, the catalytic to preserve strand­specific information. Briefly, pA­Tn5 loaded subunit of DNA primase Pol a (30, 31). We show that Ctf4 mutants with one oligonucleotide adaptor was targeted to specific chromatin that cannot bind Pol1 or Pol1 mutant that cannot bind Ctf4 com­ regions by antibodies against a protein of interest. After addition of promise the transfer of parental H3­H4 in a manner similar to the Mg2+, pA­Tn5 digested and tagmented chromatin locally (Fig. 1A). Mcm2 mutant defective in binding to H3­H4 (25). However, it is A second adaptor is then ligated to the 3′ end of the purified DNA still not known how Pol1 modulates parental histone transfer. Re­ fragments so that the strand­specific information is preserved. A cent studies indicate that both yeast Pol1 and mammalian POLA1 small fraction of the DNA was processed directly for library
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