The intra-S phase checkpoint targets Dna2 to prevent stalled replication forks from reversing

When replication forks stall at damaged bases or upon nucleotide depletion, the intra-S phase checkpoint ensures they are stabilized and can restart. In intra-S checkpoint-deficient budding yeast, stalling forks collapse, and ∼10% form pathogenic chicken foot structures, contributing to incomplete r...

Celý popis

Uloženo v:

Podrobná bibliografie
Vydáno v:	Cell Ročník 149; číslo 6; s. 1221
Hlavní autoři:	Hu, Jiazhi, Sun, Lei, Shen, Fenfen, Chen, Yufei, Hua, Yu, Liu, Yang, Zhang, Mian, Hu, Yiren, Wang, Qingsong, Xu, Wei, Sun, Fei, Ji, Jianguo, Murray, Johanne M, Carr, Antony M, Kong, Daochun
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 08.06.2012
Témata:	Checkpoint Kinase 2 DNA Replication Epistasis, Genetic Flap Endonucleases - metabolism Genomic Instability Phosphorylation Protein Serine-Threonine Kinases - metabolism S Phase Cell Cycle Checkpoints Schizosaccharomyces - cytology Schizosaccharomyces - genetics Schizosaccharomyces - metabolism Schizosaccharomyces pombe Proteins - metabolism
ISSN:	1097-4172, 1097-4172
On-line přístup:	Zjistit podrobnosti o přístupu
Tagy:	Přidat tag Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!

Abstract	When replication forks stall at damaged bases or upon nucleotide depletion, the intra-S phase checkpoint ensures they are stabilized and can restart. In intra-S checkpoint-deficient budding yeast, stalling forks collapse, and ∼10% form pathogenic chicken foot structures, contributing to incomplete replication and cell death (Lopes et al., 2001; Sogo et al., 2002; Tercero and Diffley, 2001). Using fission yeast, we report that the Cds1(Chk2) effector kinase targets Dna2 on S220 to regulate, both in vivo and in vitro, Dna2 association with stalled replication forks in chromatin. We demonstrate that Dna2-S220 phosphorylation and the nuclease activity of Dna2 are required to prevent fork reversal. Consistent with this, Dna2 can efficiently cleave obligate precursors of fork regression-regressed leading or lagging strands-on model replication forks. We propose that Dna2 cleavage of regressed nascent strands prevents fork reversal and thus stabilizes stalled forks to maintain genome stability during replication stress.
AbstractList	When replication forks stall at damaged bases or upon nucleotide depletion, the intra-S phase checkpoint ensures they are stabilized and can restart. In intra-S checkpoint-deficient budding yeast, stalling forks collapse, and ∼10% form pathogenic chicken foot structures, contributing to incomplete replication and cell death (Lopes et al., 2001; Sogo et al., 2002; Tercero and Diffley, 2001). Using fission yeast, we report that the Cds1(Chk2) effector kinase targets Dna2 on S220 to regulate, both in vivo and in vitro, Dna2 association with stalled replication forks in chromatin. We demonstrate that Dna2-S220 phosphorylation and the nuclease activity of Dna2 are required to prevent fork reversal. Consistent with this, Dna2 can efficiently cleave obligate precursors of fork regression-regressed leading or lagging strands-on model replication forks. We propose that Dna2 cleavage of regressed nascent strands prevents fork reversal and thus stabilizes stalled forks to maintain genome stability during replication stress. When replication forks stall at damaged bases or upon nucleotide depletion, the intra-S phase checkpoint ensures they are stabilized and can restart. In intra-S checkpoint-deficient budding yeast, stalling forks collapse, and ∼10% form pathogenic chicken foot structures, contributing to incomplete replication and cell death (Lopes et al., 2001; Sogo et al., 2002; Tercero and Diffley, 2001). Using fission yeast, we report that the Cds1(Chk2) effector kinase targets Dna2 on S220 to regulate, both in vivo and in vitro, Dna2 association with stalled replication forks in chromatin. We demonstrate that Dna2-S220 phosphorylation and the nuclease activity of Dna2 are required to prevent fork reversal. Consistent with this, Dna2 can efficiently cleave obligate precursors of fork regression-regressed leading or lagging strands-on model replication forks. We propose that Dna2 cleavage of regressed nascent strands prevents fork reversal and thus stabilizes stalled forks to maintain genome stability during replication stress.When replication forks stall at damaged bases or upon nucleotide depletion, the intra-S phase checkpoint ensures they are stabilized and can restart. In intra-S checkpoint-deficient budding yeast, stalling forks collapse, and ∼10% form pathogenic chicken foot structures, contributing to incomplete replication and cell death (Lopes et al., 2001; Sogo et al., 2002; Tercero and Diffley, 2001). Using fission yeast, we report that the Cds1(Chk2) effector kinase targets Dna2 on S220 to regulate, both in vivo and in vitro, Dna2 association with stalled replication forks in chromatin. We demonstrate that Dna2-S220 phosphorylation and the nuclease activity of Dna2 are required to prevent fork reversal. Consistent with this, Dna2 can efficiently cleave obligate precursors of fork regression-regressed leading or lagging strands-on model replication forks. We propose that Dna2 cleavage of regressed nascent strands prevents fork reversal and thus stabilizes stalled forks to maintain genome stability during replication stress.
Author	Shen, Fenfen Sun, Fei Zhang, Mian Kong, Daochun Hu, Yiren Liu, Yang Ji, Jianguo Xu, Wei Murray, Johanne M Wang, Qingsong Chen, Yufei Hua, Yu Sun, Lei Hu, Jiazhi Carr, Antony M
Author_xml	– sequence: 1 givenname: Jiazhi surname: Hu fullname: Hu, Jiazhi organization: The National Laboratory of Protein Engineering and Plant Genetic Engineering, The College of Life Sciences, Peking University, Beijing, China – sequence: 2 givenname: Lei surname: Sun fullname: Sun, Lei – sequence: 3 givenname: Fenfen surname: Shen fullname: Shen, Fenfen – sequence: 4 givenname: Yufei surname: Chen fullname: Chen, Yufei – sequence: 5 givenname: Yu surname: Hua fullname: Hua, Yu – sequence: 6 givenname: Yang surname: Liu fullname: Liu, Yang – sequence: 7 givenname: Mian surname: Zhang fullname: Zhang, Mian – sequence: 8 givenname: Yiren surname: Hu fullname: Hu, Yiren – sequence: 9 givenname: Qingsong surname: Wang fullname: Wang, Qingsong – sequence: 10 givenname: Wei surname: Xu fullname: Xu, Wei – sequence: 11 givenname: Fei surname: Sun fullname: Sun, Fei – sequence: 12 givenname: Jianguo surname: Ji fullname: Ji, Jianguo – sequence: 13 givenname: Johanne M surname: Murray fullname: Murray, Johanne M – sequence: 14 givenname: Antony M surname: Carr fullname: Carr, Antony M – sequence: 15 givenname: Daochun surname: Kong fullname: Kong, Daochun
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/22682245$$D View this record in MEDLINE/PubMed
BookMark	eNpNkE9Lw0AUxBepWFv9Ah5kj14S326ySXqU-hcKHqxHCS-bt23aNBt3t4Lf3hQryBxmGH7MYSZs1NmOGLsSEAsQ2e0m1tS2sQQhY0hjSOCEnQuY5VEqcjn6l8ds4v0GAAql1BkbS5kVUqbqnH0s18SbLjiM3ni_Rk9cr0lvezuUPKBbUfD8vkPJg-W9oy8aeh-wbanmjvq20Rga23Fj3dZz4-yOHyjnm251wU4Ntp4ujz5l748Py_lztHh9epnfLSKdqjxEGekEiHJUiDKRqjKYZbNaVaDyDAcRFFpXqEQt6yKfVQWmlSkANWXGJEZO2c3vbu_s5558KHeNP5yDHdm9LwVIgDRXQg3o9RHdVzuqy941O3Tf5d8l8gcabWex
CitedBy_id	crossref_primary_10_1093_nar_gkaa524 crossref_primary_10_1242_jcs_260828 crossref_primary_10_1080_13543784_2017_1360275 crossref_primary_10_1016_j_ebiom_2016_02_043 crossref_primary_10_3390_biomedicines11051450 crossref_primary_10_1016_j_cell_2012_05_021 crossref_primary_10_1074_jbc_RA118_005415 crossref_primary_10_1038_s41586_025_09470_5 crossref_primary_10_1093_nar_gkab344 crossref_primary_10_1007_s00294_020_01106_7 crossref_primary_10_1038_ncomms13157 crossref_primary_10_1093_nar_gkaf707 crossref_primary_10_1016_j_pbiomolbio_2021_03_007 crossref_primary_10_1038_nrm3935 crossref_primary_10_3390_biom5032123 crossref_primary_10_1128_JVI_03396_12 crossref_primary_10_3390_genes7080048 crossref_primary_10_1016_j_pbiomolbio_2020_11_005 crossref_primary_10_1016_j_dnarep_2022_103418 crossref_primary_10_4161_cc_28476 crossref_primary_10_1007_s11427_014_4631_4 crossref_primary_10_15252_embj_2019101516 crossref_primary_10_1007_s00412_016_0573_x crossref_primary_10_1073_pnas_1300390110 crossref_primary_10_1038_ncb2897 crossref_primary_10_1074_jbc_M117_781211 crossref_primary_10_4161_cc_22807 crossref_primary_10_1016_j_dnarep_2018_08_017 crossref_primary_10_1074_jbc_M116_745646 crossref_primary_10_1016_j_bbrc_2013_05_072 crossref_primary_10_1093_nar_gkz1101 crossref_primary_10_15252_embr_201744910 crossref_primary_10_1534_g3_114_011346 crossref_primary_10_1038_nsmb_3163 crossref_primary_10_1101_gad_204750_112 crossref_primary_10_1042_BST20180308 crossref_primary_10_1038_s41594_022_00871_y crossref_primary_10_1360_SSV_2025_0085 crossref_primary_10_1128_MCB_00033_20 crossref_primary_10_1016_j_molcel_2019_05_026 crossref_primary_10_3390_cimb47090756 crossref_primary_10_1007_s42764_020_00028_5 crossref_primary_10_1128_MCB_01077_14 crossref_primary_10_3390_ijms22083984 crossref_primary_10_1002_path_4828 crossref_primary_10_1093_nar_gkad624 crossref_primary_10_1038_s41467_023_43494_7 crossref_primary_10_1093_nar_gkw858 crossref_primary_10_1111_bcp_12139 crossref_primary_10_1074_jbc_M112_418715 crossref_primary_10_1182_bloodadvances_2019000391 crossref_primary_10_1038_oncsis_2017_15 crossref_primary_10_1073_pnas_2413732122 crossref_primary_10_7554_eLife_18574 crossref_primary_10_1016_j_molcel_2023_02_008 crossref_primary_10_1038_s42003_020_1048_4 crossref_primary_10_1016_j_gde_2012_11_009 crossref_primary_10_1016_j_molcel_2021_05_027 crossref_primary_10_1073_pnas_2019183118 crossref_primary_10_3389_fgene_2018_00390 crossref_primary_10_1242_jcs_152678 crossref_primary_10_3390_genes4030388 crossref_primary_10_15252_embj_201796729 crossref_primary_10_1093_nar_gkz537 crossref_primary_10_1016_j_dnarep_2017_09_001 crossref_primary_10_1016_j_tcb_2022_06_007 crossref_primary_10_1074_jbc_M116_755991 crossref_primary_10_1016_j_dnarep_2022_103332 crossref_primary_10_1093_nar_gkaa054 crossref_primary_10_1016_j_molcel_2017_05_001 crossref_primary_10_1016_j_chemosphere_2017_06_049 crossref_primary_10_1016_j_molcel_2021_05_014 crossref_primary_10_1038_s10038_022_01075_4 crossref_primary_10_1016_j_dnarep_2015_04_009 crossref_primary_10_1101_gad_336446_120 crossref_primary_10_1007_s00412_017_0658_1 crossref_primary_10_1007_s00412_013_0398_9 crossref_primary_10_1371_journal_pgen_1004594 crossref_primary_10_3390_cells14060442 crossref_primary_10_1534_genetics_116_191536 crossref_primary_10_1016_j_semcdb_2020_07_004 crossref_primary_10_1074_jbc_M116_758599 crossref_primary_10_1007_s00412_014_0471_z crossref_primary_10_1371_journal_pgen_1011044 crossref_primary_10_1016_j_cell_2021_01_048 crossref_primary_10_1073_pnas_1821475116 crossref_primary_10_1038_s41467_018_07378_5 crossref_primary_10_1093_nar_gkv836 crossref_primary_10_1126_sciadv_adr3673 crossref_primary_10_15252_embr_201846263 crossref_primary_10_4161_cc_22215 crossref_primary_10_1146_annurev_biochem_013118_110644 crossref_primary_10_7554_eLife_09832 crossref_primary_10_1016_j_semcdb_2014_03_017 crossref_primary_10_1101_gad_213306_113 crossref_primary_10_3390_ijms160510870 crossref_primary_10_1016_j_molcel_2015_12_016 crossref_primary_10_1016_j_molcel_2021_04_006 crossref_primary_10_1128_microbiolspec_FUNK_0025_2016 crossref_primary_10_1093_nar_gkae1159 crossref_primary_10_1091_mbc_E19_03_0156 crossref_primary_10_1093_nar_gkae192 crossref_primary_10_1038_cdd_2016_124 crossref_primary_10_1038_s42003_019_0428_0 crossref_primary_10_1038_s41467_022_32583_8 crossref_primary_10_3390_biom3010039 crossref_primary_10_1007_s00018_017_2474_4 crossref_primary_10_3390_genes8020074 crossref_primary_10_1016_j_dnarep_2015_04_026 crossref_primary_10_1093_nar_gkt820 crossref_primary_10_1534_g3_115_019208 crossref_primary_10_1038_s41586_018_0769_8 crossref_primary_10_1186_s13059_021_02390_3 crossref_primary_10_3390_genes8010037 crossref_primary_10_1093_abbs_gmw043 crossref_primary_10_1371_journal_pone_0092936 crossref_primary_10_1534_genetics_118_300809 crossref_primary_10_1371_journal_pgen_1008933 crossref_primary_10_1093_nar_gkaa562 crossref_primary_10_1093_nar_gku190 crossref_primary_10_1016_j_molcel_2014_09_013 crossref_primary_10_1083_jcb_201406100
ContentType	Journal Article
Copyright	Copyright © 2012 Elsevier Inc. All rights reserved.
Copyright_xml	– notice: Copyright © 2012 Elsevier Inc. All rights reserved.
DBID	CGR CUY CVF ECM EIF NPM 7X8
DOI	10.1016/j.cell.2012.04.030
DatabaseName	Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic
DatabaseTitle	MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic
DatabaseTitleList	MEDLINE MEDLINE - Academic
Database_xml	– sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database
DeliveryMethod	no_fulltext_linktorsrc
Discipline	Biology
EISSN	1097-4172
ExternalDocumentID	22682245
Genre	Research Support, Non-U.S. Gov't Journal Article
GrantInformation_xml	– fundername: Medical Research Council grantid: G600233 – fundername: Cancer Research UK grantid: C9601/A9484 – fundername: Medical Research Council grantid: G1100074 – fundername: Medical Research Council grantid: G0901011
GroupedDBID	--- --K -DZ -ET -~X 0R~ 0WA 1RT 1~5 29B 2FS 2WC 3EH 4.4 457 4G. 53G 5GY 5RE 5VS 62- 6J9 7-5 85S 9M8 AAEDT AAEDW AAFWJ AAHBH AAIKJ AAKRW AAKUH AALRI AAMRU AAQFI AAVLU AAXUO AAYJJ AAYWO ABCQX ABDGV ABJNI ABMAC ABOCM ACGFO ACGFS ACNCT ACVFH ADBBV ADCNI ADEZE ADVLN ADXHL AEFWE AENEX AEUPX AEXQZ AFPUW AFTJW AGCQF AGHFR AGHSJ AGKMS AHHHB AIDAL AIGII AITUG AKAPO AKBMS AKRWK AKYEP ALMA_UNASSIGNED_HOLDINGS AMRAJ APXCP ASPBG AVWKF AZFZN BAWUL CGR CS3 CUY CVF DIK DU5 E3Z EBS ECM EFKBS EIF EJD F5P FCP FDB FIRID HH5 HZ~ IH2 IHE IXB J1W JIG K-O KOO KQ8 L7B LX5 M3Z M41 N9A NPM O-L O9- OK1 P2P RIG RNS ROL RPZ SCP SDG SDP SES SSZ TAE TN5 TR2 TWZ UKR UPT WH7 YYQ YZZ ZCA ZY4 7X8
ID	FETCH-LOGICAL-c457t-6ec30ee7a5aa2325bfa669d5b0576a6a6e08ccba51d2d879b8a4bf80ace6ff3f2
IEDL.DBID	7X8
ISICitedReferencesCount	138
ISICitedReferencesURI	http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000305119600008&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D
ISSN	1097-4172
IngestDate	Sat Sep 27 19:00:02 EDT 2025 Mon Jul 21 05:20:51 EDT 2025
IsDoiOpenAccess	false
IsOpenAccess	true
IsPeerReviewed	true
IsScholarly	true
Issue	6
Language	English
License	Copyright © 2012 Elsevier Inc. All rights reserved.
LinkModel	DirectLink
MergedId	FETCHMERGED-LOGICAL-c457t-6ec30ee7a5aa2325bfa669d5b0576a6a6e08ccba51d2d879b8a4bf80ace6ff3f2
Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
OpenAccessLink	https://dx.doi.org/10.1016/j.cell.2012.04.030
PMID	22682245
PQID	1020047515
PQPubID	23479
ParticipantIDs	proquest_miscellaneous_1020047515 pubmed_primary_22682245
PublicationCentury	2000
PublicationDate	2012-06-08
PublicationDateYYYYMMDD	2012-06-08
PublicationDate_xml	– month: 06 year: 2012 text: 2012-06-08 day: 08
PublicationDecade	2010
PublicationPlace	United States
PublicationPlace_xml	– name: United States
PublicationTitle	Cell
PublicationTitleAlternate	Cell
PublicationYear	2012
References	22682239 - Cell. 2012 Jun 8;149(6):1181-3. doi: 10.1016/j.cell.2012.05.021.
References_xml	– reference: 22682239 - Cell. 2012 Jun 8;149(6):1181-3. doi: 10.1016/j.cell.2012.05.021.
SSID	ssj0008555
Score	2.448126
Snippet	When replication forks stall at damaged bases or upon nucleotide depletion, the intra-S phase checkpoint ensures they are stabilized and can restart. In...
SourceID	proquest pubmed
SourceType	Aggregation Database Index Database
StartPage	1221
SubjectTerms	Checkpoint Kinase 2 DNA Replication Epistasis, Genetic Flap Endonucleases - metabolism Genomic Instability Phosphorylation Protein Serine-Threonine Kinases - metabolism S Phase Cell Cycle Checkpoints Schizosaccharomyces - cytology Schizosaccharomyces - genetics Schizosaccharomyces - metabolism Schizosaccharomyces pombe Proteins - metabolism
Title	The intra-S phase checkpoint targets Dna2 to prevent stalled replication forks from reversing
URI	https://www.ncbi.nlm.nih.gov/pubmed/22682245 https://www.proquest.com/docview/1020047515
Volume	149
WOSCitedRecordID	wos000305119600008&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D
hasFullText
inHoldings	1
isFullTextHit
isPrint
link	http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV3dS8MwEA_qFHzx-2N-EcHXQJe2SfYkog5fHAMV9iIjSS84Ntq6TsH_3kvauSdBkEIfSkpL7pL7cffL_Qi5SjLd0YmImVUxsMTyjCluOBMchNLW1zx1EJuQ_b4aDruDJuFWNbTKxZ4YNuqssD5Hjqvb21Ni-L0u35lXjfLV1UZCY5W0YoQy3qvlcNktXKVB9dR_kCUYqZtDMzW_yyfGPbWLh1ancfQ7xAyhprf935_cIVsNyKQ3tVfskhXI98hGLTv5tU9e0Tfo2Gd12RMt3zCOUTSdnZQFPqQ1N7yid7nmdF7Qsm7yRBFGTqeQ0Rn8lLwpIt5JRf0RFepHhcTDAXnp3T_fPrBGZoHZJJVzJsDGEYDUqdaIr1LjtBDdLDUI5YTGCyJlrdFpJ-OZkl2jdGKcirQF4Vzs-CFZy4scjgmNuQKLEMxFgMggkUqYCGIjnTYCjFFtcrmYtxG6sTeBzqH4qEbLmWuTo3ryR2Xdb2OECNFzXdOTP7x9Sja9TQOZS52RlsNFDOdk3X7Ox9XsIvgH3vuDx28WxMZ4
linkProvider	ProQuest
openUrl	ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+intra-S+phase+checkpoint+targets+Dna2+to+prevent+stalled+replication+forks+from+reversing&rft.jtitle=Cell&rft.au=Hu%2C+Jiazhi&rft.au=Sun%2C+Lei&rft.au=Shen%2C+Fenfen&rft.au=Chen%2C+Yufei&rft.date=2012-06-08&rft.eissn=1097-4172&rft.volume=149&rft.issue=6&rft.spage=1221&rft_id=info:doi/10.1016%2Fj.cell.2012.04.030&rft_id=info%3Apmid%2F22682245&rft_id=info%3Apmid%2F22682245&rft.externalDocID=22682245
thumbnail_l	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1097-4172&client=summon
thumbnail_m	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1097-4172&client=summon
thumbnail_s	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1097-4172&client=summon