APLF facilitates interstrand DNA crosslink repair and replication fork protection to confer cisplatin resistance
Replication stress converts the stalled forks into reversed forks, which is an important protection mechanism to prevent fork degradation and collapse into poisonous DNA double-strand breaks (DSBs). Paradoxically, the mechanism also acts in cancer cells to contribute to chemoresistance against vario...
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| Veröffentlicht in: | Nucleic acids research 2024-06, Vol.52 (10), p.5676-5697 |
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| creator | Wu, Cheng-Kuei Shiu, Jia-Lin Wu, Chao-Liang Hung, Chi-Feng Ho, Yen-Chih Chen, Yen-Tzu Tung, Sheng-Yung Yeh, Cheng-Fa Shen, Che-Hung Liaw, Hungjiun Su, Wen-Pin |
| description | Replication stress converts the stalled forks into reversed forks, which is an important protection mechanism to prevent fork degradation and collapse into poisonous DNA double-strand breaks (DSBs). Paradoxically, the mechanism also acts in cancer cells to contribute to chemoresistance against various DNA-damaging agents. PARP1 binds to and is activated by stalled forks to facilitate fork reversal. Aprataxin and polynucleotide kinase/phosphatase-like factor (APLF) binds to PARP1 through the poly(ADP-ribose) zinc finger (PBZ) domain and is known to be involved in non-homologous end joining (NHEJ). Here, we identify a novel function of APLF involved in interstrand DNA crosslink (ICL) repair and fork protection. We demonstrate that PARP1 activity facilitates the APLF recruitment to stalled forks, enabling the FANCD2 recruitment to stalled forks. The depletion of APLF sensitizes cells to cisplatin, impairs ICL repair, reduces the FANCD2 recruitment to stalled forks, and results in nascent DNA degradation by MRE11 nucleases. Additionally, cisplatin-resistant cancer cells show high levels of APLF and homologous recombination-related gene expression. The depletion of APLF sensitizes cells to cisplatin and results in fork instability. Our results reveal the novel function of APLF to facilitate ICL repair and fork protection, thereby contributing to cisplatin-resistant phenotypes of cancer cells. |
| doi_str_mv | 10.1093/nar/gkae211 |
| format | Article |
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Paradoxically, the mechanism also acts in cancer cells to contribute to chemoresistance against various DNA-damaging agents. PARP1 binds to and is activated by stalled forks to facilitate fork reversal. Aprataxin and polynucleotide kinase/phosphatase-like factor (APLF) binds to PARP1 through the poly(ADP-ribose) zinc finger (PBZ) domain and is known to be involved in non-homologous end joining (NHEJ). Here, we identify a novel function of APLF involved in interstrand DNA crosslink (ICL) repair and fork protection. We demonstrate that PARP1 activity facilitates the APLF recruitment to stalled forks, enabling the FANCD2 recruitment to stalled forks. The depletion of APLF sensitizes cells to cisplatin, impairs ICL repair, reduces the FANCD2 recruitment to stalled forks, and results in nascent DNA degradation by MRE11 nucleases. Additionally, cisplatin-resistant cancer cells show high levels of APLF and homologous recombination-related gene expression. The depletion of APLF sensitizes cells to cisplatin and results in fork instability. Our results reveal the novel function of APLF to facilitate ICL repair and fork protection, thereby contributing to cisplatin-resistant phenotypes of cancer cells.</description><identifier>ISSN: 0305-1048</identifier><identifier>ISSN: 1362-4962</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkae211</identifier><identifier>PMID: 38520407</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Antineoplastic Agents - pharmacology ; Cell Line, Tumor ; Cisplatin - pharmacology ; DNA - genetics ; DNA - metabolism ; DNA Breaks, Double-Stranded ; DNA Damage ; DNA Repair ; DNA Replication - drug effects ; DNA-(Apurinic or Apyrimidinic Site) Lyase ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Drug Resistance, Neoplasm - genetics ; Fanconi Anemia Complementation Group D2 Protein - genetics ; Fanconi Anemia Complementation Group D2 Protein - metabolism ; Genome Integrity, Repair and ; Humans ; Poly (ADP-Ribose) Polymerase-1 - genetics ; Poly (ADP-Ribose) Polymerase-1 - metabolism ; Poly-ADP-Ribose Binding Proteins</subject><ispartof>Nucleic acids research, 2024-06, Vol.52 (10), p.5676-5697</ispartof><rights>The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.</rights><rights>The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research. 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c340t-719487098e3bbf58a0b725eada800986e615214b11f628093d1b7ba9c4bc82f43</cites><orcidid>0000-0003-0863-203X ; 0000-0002-3481-709X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11162786/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11162786/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38520407$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Cheng-Kuei</creatorcontrib><creatorcontrib>Shiu, Jia-Lin</creatorcontrib><creatorcontrib>Wu, Chao-Liang</creatorcontrib><creatorcontrib>Hung, Chi-Feng</creatorcontrib><creatorcontrib>Ho, Yen-Chih</creatorcontrib><creatorcontrib>Chen, Yen-Tzu</creatorcontrib><creatorcontrib>Tung, Sheng-Yung</creatorcontrib><creatorcontrib>Yeh, Cheng-Fa</creatorcontrib><creatorcontrib>Shen, Che-Hung</creatorcontrib><creatorcontrib>Liaw, Hungjiun</creatorcontrib><creatorcontrib>Su, Wen-Pin</creatorcontrib><title>APLF facilitates interstrand DNA crosslink repair and replication fork protection to confer cisplatin resistance</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Replication stress converts the stalled forks into reversed forks, which is an important protection mechanism to prevent fork degradation and collapse into poisonous DNA double-strand breaks (DSBs). Paradoxically, the mechanism also acts in cancer cells to contribute to chemoresistance against various DNA-damaging agents. PARP1 binds to and is activated by stalled forks to facilitate fork reversal. Aprataxin and polynucleotide kinase/phosphatase-like factor (APLF) binds to PARP1 through the poly(ADP-ribose) zinc finger (PBZ) domain and is known to be involved in non-homologous end joining (NHEJ). Here, we identify a novel function of APLF involved in interstrand DNA crosslink (ICL) repair and fork protection. We demonstrate that PARP1 activity facilitates the APLF recruitment to stalled forks, enabling the FANCD2 recruitment to stalled forks. The depletion of APLF sensitizes cells to cisplatin, impairs ICL repair, reduces the FANCD2 recruitment to stalled forks, and results in nascent DNA degradation by MRE11 nucleases. Additionally, cisplatin-resistant cancer cells show high levels of APLF and homologous recombination-related gene expression. The depletion of APLF sensitizes cells to cisplatin and results in fork instability. Our results reveal the novel function of APLF to facilitate ICL repair and fork protection, thereby contributing to cisplatin-resistant phenotypes of cancer cells.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Cisplatin - pharmacology</subject><subject>DNA - genetics</subject><subject>DNA - metabolism</subject><subject>DNA Breaks, Double-Stranded</subject><subject>DNA Damage</subject><subject>DNA Repair</subject><subject>DNA Replication - drug effects</subject><subject>DNA-(Apurinic or Apyrimidinic Site) Lyase</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Fanconi Anemia Complementation Group D2 Protein - genetics</subject><subject>Fanconi Anemia Complementation Group D2 Protein - metabolism</subject><subject>Genome Integrity, Repair and</subject><subject>Humans</subject><subject>Poly (ADP-Ribose) Polymerase-1 - genetics</subject><subject>Poly (ADP-Ribose) Polymerase-1 - metabolism</subject><subject>Poly-ADP-Ribose Binding Proteins</subject><issn>0305-1048</issn><issn>1362-4962</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUFvGyEQhVHUKnbdnHKPOFaqtmFYdpc9RZZbt5WsJIf0jFg8mxCvYQM4Uv99cexE6YmB9-kNM4-Qc2DfgLXlpdPh8n6jkQOckCmUNS9EW_MPZMpKVhXAhJyQTzE-MgYCKnFKJqWsOBOsmZJxfrta0l4bO9ikE0ZqXcIQU9BuTb9fz6kJPsbBug0NOGob6F7I5WCNTtY72vuwoWPwCc3LPXlqvOsxUGPjOGTIZT7amLQz-Jl87PUQ8ex4zsif5Y-7xa9idfPz92K-KkwpWCoaaIVsWCux7Lq-kpp1Da9Qr7Vk-bXGGioOogPoay7zGtbQNZ1ujeiM5L0oZ-Tq4Dvuui2uDbo80qDGYLc6_FVeW_W_4uyDuvfPCgBq3sg6O3w5OgT_tMOY1NZGg8OgHfpdVLxtBGNNK3lGvx7Ql2UF7N_6AFP7kFQOSR1DyvTF-6-9sa-plP8ANCqRIA</recordid><startdate>20240610</startdate><enddate>20240610</enddate><creator>Wu, Cheng-Kuei</creator><creator>Shiu, Jia-Lin</creator><creator>Wu, Chao-Liang</creator><creator>Hung, Chi-Feng</creator><creator>Ho, Yen-Chih</creator><creator>Chen, Yen-Tzu</creator><creator>Tung, Sheng-Yung</creator><creator>Yeh, Cheng-Fa</creator><creator>Shen, Che-Hung</creator><creator>Liaw, Hungjiun</creator><creator>Su, Wen-Pin</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0863-203X</orcidid><orcidid>https://orcid.org/0000-0002-3481-709X</orcidid></search><sort><creationdate>20240610</creationdate><title>APLF facilitates interstrand DNA crosslink repair and replication fork protection to confer cisplatin resistance</title><author>Wu, Cheng-Kuei ; Shiu, Jia-Lin ; Wu, Chao-Liang ; Hung, Chi-Feng ; Ho, Yen-Chih ; Chen, Yen-Tzu ; Tung, Sheng-Yung ; Yeh, Cheng-Fa ; Shen, Che-Hung ; Liaw, Hungjiun ; Su, Wen-Pin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c340t-719487098e3bbf58a0b725eada800986e615214b11f628093d1b7ba9c4bc82f43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Cisplatin - pharmacology</topic><topic>DNA - genetics</topic><topic>DNA - metabolism</topic><topic>DNA Breaks, Double-Stranded</topic><topic>DNA Damage</topic><topic>DNA Repair</topic><topic>DNA Replication - drug effects</topic><topic>DNA-(Apurinic or Apyrimidinic Site) Lyase</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Fanconi Anemia Complementation Group D2 Protein - genetics</topic><topic>Fanconi Anemia Complementation Group D2 Protein - metabolism</topic><topic>Genome Integrity, Repair and</topic><topic>Humans</topic><topic>Poly (ADP-Ribose) Polymerase-1 - genetics</topic><topic>Poly (ADP-Ribose) Polymerase-1 - metabolism</topic><topic>Poly-ADP-Ribose Binding Proteins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Cheng-Kuei</creatorcontrib><creatorcontrib>Shiu, Jia-Lin</creatorcontrib><creatorcontrib>Wu, Chao-Liang</creatorcontrib><creatorcontrib>Hung, Chi-Feng</creatorcontrib><creatorcontrib>Ho, Yen-Chih</creatorcontrib><creatorcontrib>Chen, Yen-Tzu</creatorcontrib><creatorcontrib>Tung, Sheng-Yung</creatorcontrib><creatorcontrib>Yeh, Cheng-Fa</creatorcontrib><creatorcontrib>Shen, Che-Hung</creatorcontrib><creatorcontrib>Liaw, Hungjiun</creatorcontrib><creatorcontrib>Su, Wen-Pin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wu, Cheng-Kuei</au><au>Shiu, Jia-Lin</au><au>Wu, Chao-Liang</au><au>Hung, Chi-Feng</au><au>Ho, Yen-Chih</au><au>Chen, Yen-Tzu</au><au>Tung, Sheng-Yung</au><au>Yeh, Cheng-Fa</au><au>Shen, Che-Hung</au><au>Liaw, Hungjiun</au><au>Su, Wen-Pin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>APLF facilitates interstrand DNA crosslink repair and replication fork protection to confer cisplatin resistance</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2024-06-10</date><risdate>2024</risdate><volume>52</volume><issue>10</issue><spage>5676</spage><epage>5697</epage><pages>5676-5697</pages><issn>0305-1048</issn><issn>1362-4962</issn><eissn>1362-4962</eissn><abstract>Replication stress converts the stalled forks into reversed forks, which is an important protection mechanism to prevent fork degradation and collapse into poisonous DNA double-strand breaks (DSBs). Paradoxically, the mechanism also acts in cancer cells to contribute to chemoresistance against various DNA-damaging agents. PARP1 binds to and is activated by stalled forks to facilitate fork reversal. Aprataxin and polynucleotide kinase/phosphatase-like factor (APLF) binds to PARP1 through the poly(ADP-ribose) zinc finger (PBZ) domain and is known to be involved in non-homologous end joining (NHEJ). Here, we identify a novel function of APLF involved in interstrand DNA crosslink (ICL) repair and fork protection. We demonstrate that PARP1 activity facilitates the APLF recruitment to stalled forks, enabling the FANCD2 recruitment to stalled forks. The depletion of APLF sensitizes cells to cisplatin, impairs ICL repair, reduces the FANCD2 recruitment to stalled forks, and results in nascent DNA degradation by MRE11 nucleases. Additionally, cisplatin-resistant cancer cells show high levels of APLF and homologous recombination-related gene expression. The depletion of APLF sensitizes cells to cisplatin and results in fork instability. Our results reveal the novel function of APLF to facilitate ICL repair and fork protection, thereby contributing to cisplatin-resistant phenotypes of cancer cells.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>38520407</pmid><doi>10.1093/nar/gkae211</doi><tpages>22</tpages><orcidid>https://orcid.org/0000-0003-0863-203X</orcidid><orcidid>https://orcid.org/0000-0002-3481-709X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Antineoplastic Agents - pharmacology Cell Line, Tumor Cisplatin - pharmacology DNA - genetics DNA - metabolism DNA Breaks, Double-Stranded DNA Damage DNA Repair DNA Replication - drug effects DNA-(Apurinic or Apyrimidinic Site) Lyase DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Drug Resistance, Neoplasm - genetics Fanconi Anemia Complementation Group D2 Protein - genetics Fanconi Anemia Complementation Group D2 Protein - metabolism Genome Integrity, Repair and Humans Poly (ADP-Ribose) Polymerase-1 - genetics Poly (ADP-Ribose) Polymerase-1 - metabolism Poly-ADP-Ribose Binding Proteins |
| title | APLF facilitates interstrand DNA crosslink repair and replication fork protection to confer cisplatin resistance |
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